CN103751193B - Include the medical composition and its use of BI 1356 and optional SGLT2 inhibitor - Google Patents

Include the medical composition and its use of BI 1356 and optional SGLT2 inhibitor Download PDF

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CN103751193B
CN103751193B CN201310655506.1A CN201310655506A CN103751193B CN 103751193 B CN103751193 B CN 103751193B CN 201310655506 A CN201310655506 A CN 201310655506A CN 103751193 B CN103751193 B CN 103751193B
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pharmaceutical composition
glucose
patient
dosage form
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CN103751193A (en
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W.伊森里克
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Boehringer Ingelheim International GmbH
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
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    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
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    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
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Abstract

The present invention relates to the pharmaceutical composition of BI 1356, pharmaceutical dosage form, it is prepared and its purposes and method for the treatment of dysbolism.

Description

Include the medical composition and its use of BI 1356 and optional SGLT2 inhibitor
The application be the applying date be on 2 11st, 2010, application No. is 201080007663.6 (international application no PCT/ EP2010/051735), entitled " to include the pharmaceutical composition and its use of BI 1356 and optional SGLT2 inhibitor The divisional application of application for a patent for invention on the way ".
Technical field
The present invention relates to include pharmaceutical composition of the BI 1356 (linagliptin) as the first active pharmaceutical ingredients. In addition, the present invention relates to the pharmaceutical dosage forms comprising the pharmaceutical composition.In addition, the present invention relates to the sides for preparing the pharmaceutical dosage form Method.In addition, the use the present invention relates to pharmaceutical composition and pharmaceutical dosage form in treating and/or preventing selected disease and medical conditions On the way, especially one or more to reduce (impaired glucose selected from type-1 diabetes mellitus, type-2 diabetes mellitus, glucose tolerance Tolerance), the illness of impaired fasting glucose (impaired fasting blood glucose) and hyperglycemia.In addition, The present invention relates to treating and/or preventing these diseases and the method for medical conditions, wherein giving the present invention to patient in need Pharmaceutical composition or pharmaceutical dosage form.
The prior art
Compound BI 1356 is DPP-IV inhibitor.Also known as the enzyme DPP-IV of CD26 (DPP IV) is known Lead to that there is serine protease of the multiple proteins of proline or alanine residue from N-terminal cracking dipeptides in N-terminal.By In this property, DPP-IV inhibitor interference includes the plasma content of the biologically active peptide of peptide GLP-1-1, and is considered as treating diabetes The promising drug of (especially type-2 diabetes mellitus).
When attempting to prepare the pharmaceutical composition of selected DPP-IV inhibitor (such as BI 1356), it has been observed that have The DPP-IV inhibitor of primary amino group or secondary amino group show with a variety of conventional excipients (such as microcrystalline cellulose, primojel, Croscarmellose sodium, tartaric acid, citric acid, glucose, fructose, sucrose, lactose, maltodextrin) incompatibility, drop Solution problem or extraction problem.Although compound itself is highly stable, with many excipient used in solid dosage forms with And reacted with the impurity of excipient, especially in tablets provide close contact when and under high excipient/drug ratios.Amino is seemingly And reduced sugar and other reactive carbonyls, and for example due to oxidation in the carboxylic-acid functional of microcrystalline cellulose surface formation Group's reaction.
These unknown difficulties are mainly seen in low needed for the surprising effectiveness due to selected inhibitor (such as BI 1356) Dosage range.The unexpected effect of these and selected DPP-IV inhibitor compound is solved therefore, it is necessary to pharmaceutical composition With related technical problem.The medicine for including BI 1356 as sole active agent composition is disclosed in WO2007/128724 Compositions.
Type-2 diabetes mellitus is the disease of increased popularity, causes life expectancy significantly to shorten because of high-frequency complication. Because of the relevant microvascular complication of diabetes, type-2 diabetes mellitus is the blindness of adult onset, kidney failure in industrial world at present And the most common cause of amputation.In addition, the presence of type-2 diabetes mellitus and 2 to 5 times of the risk increase of angiocardiopathy are related.
After disease continues for a long time, the oral therapies ultimate failure of most of type 2 diabetes patients, and become pancreas islet Plain dependence, it is necessary to daily insulin injection and carry out multiple glucose measurement daily.
In therapy (such as a line or second-line therapy and/or monotherapy or (initial or additional (add-on)) combination treatment) Common oral antidiabetic drug include but is not limited to melbine, sulfonylureas, thiazolidinedione, row how (glinides) And alpha-glucosidase restrainer.
The high rate for the treatment of failure is the relevant concurrent with prolonged hyperglycemia of height ratio in type 2 diabetes patient Disease or chronic injury (including capilary and macrovascular complications, such as nephrosis, retinopathy or neuropathy, Or cardiovascular complication) the main reason for.
Accordingly, there exist to have it is related to glycemic control, improve with disease characteristic it is related and with reduce cardiovascular morbidity And the relevant good effects of the death rate show not meeting for the method for improved security situation, drug and pharmaceutical composition simultaneously Needs.
SGLT2 inhibitor represents a kind of for treating or improving the new drug that the glycemic control of type 2 diabetes patient is researched and developed Object.The benzene derivative of glucopyranosyl substitution is disclosed as SGLT2 inhibitor in the prior art, e.g., as disclosed in WO01/ 27128、WO03/099836、WO2005/092877、WO2006/034489、WO2006/064033、WO2006/117359、 WO2006/117360、WO2007/025943、WO2007/028814、WO2007/031548、WO2007/093610、WO2007/ 128749, in WO2008/049923, WO2008/055870, WO2008/055940.It is proposed that the benzene of glucopyranosyl substitution spreads out Biology is as urinary system sugar excretion derivant and as the drug for the treatment of diabetes.
Goal of the invention
The purpose of the present invention is to provide the pharmaceutical composition comprising BI 1356, which does not show or only shows Show the sign of the BI 1356 degradation of bottom line, therefore makes it have good to splendid storage period.
Another object of the present invention is to provide the pharmaceutical composition comprising BI 1356, which contains with height It measures homogeneity and/or allows effective production in terms of the time of pharmaceutical dosage form and cost.
Another object of the present invention is to provide the pharmaceutical dosage form comprising BI 1356, which has good storage It deposits phase, short disintegration time limited, good Dissolution behaviours and/or makes BI 1356 that there is high bioavilability in patients.
Another object of the present invention is to provide the pharmaceutical compositions comprising DPPIV inhibitor and the combination of SGLT2 inhibitor Object.
Another object of the present invention is to provide the pharmaceutical composition for including BI 1356 combination S GLT2 inhibitor, the medicines Compositions do not show or only show the sign of the BI 1356 degradation of bottom line, therefore can have good to splendid storage Deposit the phase.
Another object of the present invention is to provide the pharmaceutical composition for including BI 1356 combination S GLT2 inhibitor, the medicines Compositions have high-content homogeneity and/or allow effective production in terms of the time of pharmaceutical dosage form and cost.
Another object of the present invention is to provide the pharmaceutical dosage forms for including BI 1356 combination S GLT2 inhibitor, have Good storage period, short disintegration time limited, good Dissolution behaviours and/or make BI 1356 in patients have high biological utilisation Degree.
Another object of the present invention is to provide the pharmaceutical compositions and drug that include BI 1356 combination S GLT2 inhibitor Dosage form, and provide and prevent dysbolism (especially type-2 diabetes mellitus), the progress for slowing down the dysbolism, delay or treat the generation The method for thanking to obstacle.
Another object of the present invention is to provide the pharmaceutical compositions and drug that include BI 1356 combination S GLT2 inhibitor Dosage form, and method that the glycemic control for improving patient (especially type 2 diabetes patient) in need is provided.
Another object of the present invention is to provide the pharmaceutical compositions and drug that include BI 1356 combination S GLT2 inhibitor Dosage form, although and provide improve carried out antidiabetic medicine (such as melbine or SGLT2 inhibitor or DPPIV suppression Preparation) monotherapy but the glycemic control of the still insufficient patient of glycemic control method.
Another object of the present invention is to provide the pharmaceutical compositions and drug that include BI 1356 combination S GLT2 inhibitor Dosage form, and provide and prevent, slow down or postpone glucose tolerance reduction (IGT), impaired fasting glucose (IFG), insulin resistance And/or metabolic syndrome is into the method for transforming into type-2 diabetes mellitus.
Another object of the present invention is to provide the pharmaceutical compositions and drug that include BI 1356 combination S GLT2 inhibitor Dosage form, and the illness for preventing to be selected from diabetic complication or obstacle are provided, slow down the illness or obstacle progress, delay or treatment The method of the illness or obstacle.
Another object of the present invention is to provide the pharmaceutical compositions and drug that include BI 1356 combination S GLT2 inhibitor Dosage form, and the method that weight gain is lost weight or prevented in patient in need is provided.
Another object of the present invention is to provide the new pharmaceutical compositions for respectively containing BI 1356 combination S GLT2 inhibitor Object and pharmaceutical dosage form, having treatment dysbolism, (especially diabetes, glucose tolerance reduce (IGT), impaired fasting glucose (IFG) and/or hyperglycemia) high-efficiency, have good to splendid pharmacology and/or pharmacokinetics and/or object Physicochemical property.
Another object of the present invention is to provide in cost and/or highly effective preparation drug agent of the present invention in terms of the time The method of type.
By mentioned earlier and following Examples, those skilled in the art will be evident other purposes of the present invention.
Summary of the invention
In the first aspect, the present invention is provided comprising BI 1356 as the first active pharmaceutical ingredients and one or more taxes The pharmaceutical composition of shape agent (especially one or more diluents, one or more adhesives and/or one or more disintegrants). The pharmaceutical composition of the present invention is preferably solid composite medicament, such as the solid composite medicament of oral medication.
Within the scope of the present invention, it has been found that comprising size distribution be X90<200 μm of BI 1356 is as active medicine The pharmaceutical composition of composition shows advantageous dissolution characteristic (dissolution profile) and/or good bioavilability, And with high-content homogeneity and allow effective production in terms of the time of pharmaceutical dosage form and cost.
Therefore, in another aspect, the present invention provide comprising BI 1356 as the first active pharmaceutical ingredients and one kind or The pharmaceutical composition of a variety of excipient, the wherein size distribution of first active ingredient are X90<200 μm, preferably by laser diffraction Method is determined according to volume.
In addition, within the scope of the present invention, it has been found that BI 1356 combines some excipient and do not show or only show minimum The sign of the BI 1356 degradation of limit, therefore can have good to splendid storage period.Specifically, it has been found that the present invention Purpose can to pass through described above only include that the pharmaceutical composition of diluent a kind of is realized.
In addition, within the scope of the present invention, it has been found that combined hereafter as the first active pharmaceutical ingredients comprising BI 1356 The benzene derivative of formula (I) glucopyranosyl substitution does not show as the pharmaceutical composition of SGLT2 inhibitor or only shows Show the sign of the BI 1356 degradation of bottom line, therefore can have good to splendid storage period.In view of BI 1356 Chemical property and glucopyranosyl substitution benzene derivative functional group (especially glucopyranose basic ring and its in hydroxyl), The result cannot be predicted before making the present invention.
Therefore, in another aspect, the present invention provides a kind of pharmaceutical composition, and it includes BI 1356s as active medicine Composition；The benzene derivative of formula (I) glucopyranosyl substitution
Wherein R1Indicate chlorine or methyl；And R3Indicate ethyl, acetenyl, ethyoxyl, (R)-tetrahydrofuran -3- bases oxygroup or (S)-tetrahydrofuran -3- bases oxygroup or its prodrug, as active pharmaceutical ingredients；One or more diluents；It is one or more viscous Mixture and one or more disintegrants.
Within the scope of the present invention, it has been found that comprising size distribution be 1 μm<X90<200 μm of glucopyranosyl substitution Benzene derivative show advantageous dissolution characteristic and/or good biological utilisation as the pharmaceutical composition of active pharmaceutical ingredients Degree, and with high-content homogeneity and allow effective production in terms of the time of pharmaceutical dosage form and cost.
Therefore, in another aspect, the present invention is provided comprising BI 1356 as the first active pharmaceutical ingredients and hereafter institute The benzene derivative for formula (I) glucopyranosyl substitution stated is as the second active pharmaceutical ingredients and the medicine of one or more excipient Compositions, the wherein size distribution of second active ingredient are 1 μm<X90<200 μm, preferably by laser diffractometry according to volume It determines.
The pharmaceutical composition of the present invention has high-content homogeneity and allows in pharmaceutical dosage form (such as tablet and capsule) Effective production in terms of time and cost.In addition, these pharmaceutical dosage forms (especially tablet, such as individual layer tablet or bilayer tablet) are no Display only shows the sign that the BI 1356 of bottom line is degraded, therefore can have long storage period.
Therefore, in another aspect, the present invention provides the pharmaceutical dosage form of the pharmaceutical composition comprising the present invention.Medicine of the present invention Agent type is preferably solid pharmaceutical dosage formulation, is even more preferably used for the solid pharmaceutical dosage formulation of oral medication.
In another aspect, the present invention provides the method for preparing pharmaceutical dosage form of the present invention, and this method includes one or more Granulation step, one of which or two kinds of active pharmaceutical ingredients are pelletized together with one or more excipient.
It moreover has been found that the benzene derivative of formula described below (I) glucopyranosyl substitution is combined comprising BI 1356 Pharmaceutical composition is advantageously used for preventing the dysbolism of patient, the progress for slowing down the dysbolism, delay or treat the generation Thank to obstacle, particularly for improving the glycemic control of patient, the patient is for example using the existing treatment containing oral antidiabetic drug Method but the insufficient patient of glycemic control.This opens treatment and prevents type-2 diabetes mellitus, overweight, obesity, diabetes complicated The new treatment of disease and associatcd disease state may.
According to another aspect of the present invention, it provides and prevents dysbolism in patient in need, slows down the dysbolism Progress, delay or the method for treating the dysbolism, which is selected from：Type-1 diabetes mellitus, type-2 diabetes mellitus, glucose Tolerance reduces (IGT), impaired fasting glucose (IFG), hyperglycemia, post prandial hyperglycemia, overweight, obesity and Metabolic syndrome Sign, it is characterised in that the pharmaceutical composition or pharmaceutical dosage form of contextual definition are given to patient.
According to another aspect of the present invention, provide improves glycemic control and/or reduction fasting blood in patient in need The method for starching glucose, Post-prandial plasma glucose and/or glycosylated hemoglobin HbA1c, it is characterised in that given to patient Pharmaceutical composition or pharmaceutical dosage form defined below.
The pharmaceutical composition and pharmaceutical dosage form of the present invention can also have valuable in glucose tolerance reduction (IGT), sky Disease modifying matter in terms of abdomen pathoglycemia (IFG), insulin resistance and/or the relevant disease of metabolic syndrome or illness.
According to another aspect of the present invention, it provides and prevents in patient in need, slows down, postponing or reverses glucose is resistance to Reduction (IGT), impaired fasting glucose (IFG), insulin resistance and/or metabolic syndrome are measured into the side for transforming into type-2 diabetes mellitus Method, it is characterised in that the pharmaceutical composition or pharmaceutical dosage form of contextual definition are given to patient.
By using the pharmaceutical composition and pharmaceutical dosage form of the present invention, the glycemic control of patient in need can be improved, also Those or by the increase caused by illness and/or diseases related with blood-sugar content increase can be treated.
According to another aspect of the present invention, provide in patient in need prevent illness or obstacle, slow down the illness or Obstacle progress postpones or treats the illness or the method for obstacle, and the illness or obstacle are selected from：Diabetic complication, for example, it is white interior Barrier and capilary and macrovascular diseases, such as nephropathy, retinopathy, neuropathy, tissue ischemia, diabetes, artery Hardening, myocardial infarction, acute coronary syndrome, unstable angina pectoris, stable angina cordis, apoplexy, peripheral arterial resistance Plug property disease, cardiomyopathy, heart failure, arrhythmia cordis and reangiostenosis, it is characterised in that give contextual definition to patient Pharmaceutical composition or pharmaceutical dosage form.Term " tissue ischemia " especially includes diabetic macroangiopathy, the micro- blood of diabetic keratopathy Pipe lesion, wound healing exception and diabetic ulcer.Especially can treatment of diabetic nephropathy become (such as hyperperfusion, albumen Urine and albuminuria) one or more aspects, slow down its progress or delay or prevent its breaking-out.Term " capilary and big blood Pipe disease " and " capilary and macrovascular complications " are used interchangeably in this application.
By giving pharmaceutical composition of the invention and pharmaceutical dosage form and due to the activity of SGLT2 inhibitor, crossing hyperglycemia Content will not be converted to insoluble storage form (such as fat), but the urine through patient is drained.Therefore, result is weight Do not increase or even weight loss.
According to another aspect of the present invention, it provides and weight gain or promotion body is lost weight or prevented in the patient of needs The method reduced again, it is characterised in that the pharmaceutical composition or pharmaceutical dosage form of contextual definition are given to patient.
The pharmacology of the benzene derivative replaced as the glucopyranosyl of SGLT2 inhibitor in the pharmaceutical composition of the present invention Effect is unrelated with insulin.Therefore, it is possible to improve blood glucose control in the case where not generating additional injuries to pancreatic beta cell System.By giving the pharmaceutical composition or pharmaceutical dosage form of the present invention, can postpone or prevent β cell degradations and β cell functions reduces, Such as Apoptosis or the necrosis of pancreatic beta cell.In addition, can improve or restore the function of pancreatic cell, and increase pancreatic beta cell Number and size.It may show, by that hyperglycemia can be made to interfere with the pharmaceutical composition of the present invention or pharmaceutical dosage form processing Pancreatic beta cell differentiation state and hyperplasia normalization.
According to another aspect of the present invention, provide that prevent, slow down, postpone or treat pancreas β in patient in need thin Born of the same parents degenerate and/or Pancreatic beta cells function reduces, and/or improve and/or restore the function of pancreatic beta cell, and/or restore pancreas The method of insulin secretion function, it is characterised in that the pharmaceutical composition or pharmaceutical dosage form of contextual definition are given to patient.
By giving the pharmaceutical composition and pharmaceutical dosage form of the present invention, the abnormal storage that can be reduced or inhibit fat in liver Product.Therefore, according to another aspect of the present invention, provide and prevent in patient in need, slow down, postpone or treat by liver fat The method of disease or illness caused by fat accumulation extremely, it is characterised in that patient give contextual definition pharmaceutical composition or Pharmaceutical dosage form.Disease or illness caused by liver fat extremely accumulation are especially selected from：Common fats liver (general fatty Liver), nonalcoholic fatty liver (NAFL), nonalcoholic steatohepatitis (NASH), overnutrition induce fatty liver, The fatty liver or Poisoning fatty liver that diabetes fatty liver, alcohol induce.
As a result, another aspect of the present invention provide in patient in need keep and/or improve insulin sensitivity and/ Or treat or prevent hyperinsulinemia and/or the method for insulin resistance, it is characterised in that give contextual definition to patient Pharmaceutical composition or pharmaceutical dosage form.
According to another aspect of the present invention, the pharmaceutical composition for providing the present invention is being prepared in patient in need Realize the purposes in the drug of following purpose：
The dysbolism is treated in prevention dysbolism selected from the following, the progress for slowing down the dysbolism, delay：I types Diabetes, type-2 diabetes mellitus, glucose tolerance reduce (IGT), impaired fasting glucose (IFG), hyperglycemia, postprandial hyperglycemia Disease, overweight, obesity and metabolic syndrome；Or
Improve glycemic control and/or reduces fasting plasma glucose, Post-prandial plasma glucose and/or the blood red egg of glycosylation White HbA1c；Or
Prevent, slow down, postponing or reverses glucose tolerance reduces (IGT), impaired fasting glucose (IFG), insulin resistance And/or metabolic syndrome is into transforming into type-2 diabetes mellitus；Or
Prevention illness selected from the following or obstacle slow down the illness or obstacle progress, postpone or treat the illness or barrier Hinder：Diabetic complication, such as cataract and capilary and macrovascular diseases, such as nephropathy, retinopathy, neuropathy Change, tissue ischemia, diabetes, artery sclerosis, myocardial infarction, acute coronary syndrome, unstable angina pectoris, stabilization Type angina pectoris, apoplexy, peripheral occlusive arterial disease, cardiomyopathy, heart failure, arrhythmia cordis and reangiostenosis；Or
It loses weight or prevents weight gain or promote weight loss；Or
Prevent, slow down, postpone or treat pancreatic beta cell degeneration and/or the reduction of Pancreatic beta cells function, and/or improves And/or restores the function of pancreatic beta cell and/or restore pancreatic insulin secreting function；Or
Prevent, slow down, postpone or treat disease or illness caused by liver fat extremely accumulation；Or
It keeps and/or improves insulin sensitivity and/or treat or prevent hyperinsulinemia and/or insulin resistance.
According to another aspect of the present invention, the pharmaceutical composition or pharmaceutical dosage form for providing the present invention are being prepared for context Purposes in therapeutic and Preventive Method the drug.
Definition
The pharmaceutical composition of the present invention or the term " active ingredient " of pharmaceutical dosage form or " active pharmaceutical ingredients " refer to Li La Arrange the benzene derivative of spit of fland and formula (I) glucopyranosyl substitution of the optional present invention, especially compound (I.3).
The term " body mass index " of human patients or " BMI " be defined as by kilogram in terms of weight divided by height in meters Square, the unit of such BMI is kg/m2。
The BMI that term " overweight " is defined as individual is more than 25kg/m2And it is less than 30kg/m2Illness.Term " overweight " and " fat early period " is used interchangeably.
The BMI that term " obesity " is defined as individual is equal to or more than 30kg/m2Illness.It is defined according to WHO, term fertilizer Fat disease can be classified as follows：Term " I grades of obesity " is that BMI is equal to or more than 30kg/m2But it is less than 35kg/m2Illness；Term " II grades of obesity " is that BMI is equal to or more than 35kg/m2But it is less than 40kg/m2Illness；Term " III level obesity " is BMI etc. In or more than 40kg/m2Illness.
Term " visceral obesity " is defined as measuring male's waist-to-hipratio more than or equal to 1.0 and women waist-to-hipratio is more than or Illness equal to 0.8.It defines the risk of insulin resistance and pre-diabetes development.
Term " abdominal obesity " is commonly defined as male's waistline>40 inches or 102cm and women waistline>35 inches or The illness of 94cm.For Japanese ethnic (Japanese ethnicity) or Japanese patients, abdominal obesity may be defined as man Property waistline >=85cm and women waistline >=90cm (for example, see Japanese metabolic syndrome diagnose enquiry committee (investig a ting committee for the diagnosis of metabolic syndrome in Japan))。
Term " blood glucose is normal " is defined as individual fasting plasma glucose concentration in normal range (NR), that is, is more than 70mg/dL (3.89mmol/L) and less than 100mg/dL (5.6mmol/L) the case where." empty stomach " word has the general sense of medical terminology.
Term " hyperglycemia " is defined as individual fasting plasma glucose concentration and is higher than normal range (NR), that is, is more than 100mg/dL The illness of (5.6mmol/L)." empty stomach " word has the general sense of medical terminology.
Term " hypoglycemia " is defined as individual blood sugar concentration and is less than normal range (NR), especially less than 70mg/dL The illness of (3.89mmol/L).
Term " post prandial hyperglycemia " is defined as the postprandial 2 hours blood glucose of individual or serum glucose concentration is more than 200mg/dL The illness of (11.11mmol/L).
Term " impaired fasting glucose " or " IFG " are defined as individual fasting plasma glucose concentration or Diagnostic Value of Fasting Serum concentration of glucose exists In 100 to 125mg/dl (i.e. 5.6 to 6.9mmol/l) ranges, especially greater than 110mg/dL and be less than 126mg/dl The illness of (7.00mmol/L).The fasting glucose concentration of " normal fasting glucose " individual is less than 100mg/dl, that is, is less than 5.6mmol/l。
Term " glucose tolerance reduction " or " IGT " are defined as the postprandial 2 hours blood glucose of individual or serum glucose concentration is big In 140mg/dl (7.78mmol/L) and less than the illness of 200mg/dL (11.11mmol/L).Abnormal glucose tolerance (is eaten 2 hours blood glucose or serum glucose concentration afterwards) it can be to be absorbed after empty stomach after 75g glucose 2 hours, the Portugal of every deciliter of blood plasma The blood-sugar content of grape sugar milligram number is measured.The postprandial 2 hours blood glucose or serum glucose of " normal glucose-tolerant " individual Concentration is less than 140mg/dl (7.78mmol/L).
Term " hyperinsulinemia " is defined as having insulin resistance and blood glucose is normal or the sky of the abnormal individual of blood glucose Abdomen or post-prandial serum or plasma insulin concentrations are higher than no insulin resistance and waist-to-hipratio<1.0 (males) or<0.8 (women's) The illness of normal thin individual.
Term " insulin sensitivity ", " insulin resistance improvement " or " insulin resistance reduction " it is synonymous and be used interchangeably.
Term " insulin resistance " is defined as wherein needing cycle insulin content normal anti-more than glucose is stimulated It should be to keep state (Ford ES et al., JAMA. (2002) 287 of euglycemia state:356-9).Measure insulin resistance Method is euglycemia-hyperinsulinemia clamp procedure (euglycaemic-hyperinsulinaemic clamp test).The ratio of insulin and glucose is measured in combination insulin-glucose infusion technical scope.If glucose absorption Less than the 25% of research background group of institute, then it is assumed that have insulin resistance (WHO definition).More much easier than clamp procedure is So-called mini model (minimal model), wherein during intravenous glucose tolerance test, under Fixed Time Interval The insulin and concentration of glucose in blood are measured, and thus calculates insulin resistance.It in this approach can not possibly difference liver pancreas islet Plain resistance and periphery insulin resistance.
In addition, can by evaluation the steady-state model of insulin resistance " evaluate (HOMA-IR) " score (insulin resistance can By instruction) come quantitative insulin resistance (have reaction of the insulin resistant patient to therapy), insulin sensitivity and high pancreas islet Plain mass formed by blood stasis (KatsukIA et al., Diabetes Care2001;24:362-5).It reference is also made to measure insulin sensitivity Method (Matthews et al., the Diabetologia1985,28 of HOMA indexes:412-19), Intact Islets element original and pancreas are measured Method (Forst et al., the Diabetes2003,52 (supplementary issue 1) of the ratio of island element:A459) and euglycemia clamp is studied.This Outside, it can be substituted with the possibility of insulin sensitivity to monitor Plasma adiponectin (adiponectin) content.It is calculated with following formula steady Estimation (Galvin P et al., Diabet Med1992 of state Evaluation model (the HOMA)-IR scores to insulin resistance;9:921- 8)：
HOMA-IR=[Diagnostic Value of Fasting Serum insulin (μ U/mL)] × [fasting plasma glucose (mmol/L)/22.5]
In general, evaluating insulin resistance using other parameters in daily clinical practice.Preferably, using such as patient's Triglyceride concentration, because the increase of content of triglyceride and the presence of insulin resistance have significant correlation.
Tool development IGT or IFG or the patient of type-2 diabetes mellitus tendency are that those with hyperinsulinemia and are defined as pancreas The normal person of blood glucose of insulin resistance.Typical patient with insulin resistance is general overweight or fat.If can detect insulin Resistance, then this is the strength instruction for pre-diabetes occur.Therefore, in order to keep glucose homeostasis, which may need to be good for Otherwise the insulin of 2-3 times of health individual will lead to any clinical symptoms.
The method for studying Pancreatic beta cells function resists with above for insulin sensitivity, hyperinsulinemia or insulin The method of property is similar：Can for example by measure β cell functions HOMA indexes (Matthews et al., Diabetologia1985, 28:412-19), former ratio (Forst et al., the Diabetes2003,52 (supplementary issue 1) with insulin of Intact Islets element:A459)、 Insulin/C- peptides secretion after oral glucose tolerance test or meal tolerance test, or studied by using hyperglycemia clamp And/or mini model (Stumvoll et al., Eur J Clin are established after the intravenous glucose tolerance test frequently sampled Invest2001,31:380-81) measure the improvement of β cell functions.
Term " pre-diabetes " is the illness that individual tends to develop type-2 diabetes mellitus.Pre-diabetes extend grape The definition that sugar tolerance reduces makes it include with fasting blood-glucose in the interior (J.B.Meigs etc. of high normal range (NR) (>=100mg/dL) People, Diabetes2003;52:1475-1484) and with empty stomach hyperinsulinemia (high plasma insulin concentrations) individual. American Diabetes Association (American Diabetes Association) and US National diabetes and digestion and nephrosis research Institute (National Institute of Diabetes and Digestive and Kidney Diseases) is being sent out jointly It is illustrated in the status report of entitled " the The Prevention or Delay of Type2Diabetes " of cloth and differentiates sugar early period Urine disease is to seriously threaten the science and basic medical (Diabetes Care2002 of health;25:742-749).
May the individual with insulin resistance be the individual with two or more following characteristics：1) overweight or fat, 2) hypertension, 3) hyperlipidemia, 4) one or more first degree relatives diagnosis suffer from IGT or IFG or type-2 diabetes mellitus.Meter can be passed through Calculate the insulin resistance that HOMA-IR scores determine these individuals.For purposes of the present invention, insulin resistance is defined as individual HOMA-IR scores>4.0 or HOMA-IR scores carry out normal upper limit defined in glucose and insulin analysis higher than laboratory Clinical disease.
Term " type-2 diabetes mellitus " is defined as individual fasting blood-glucose or serum glucose concentration is more than 125mg/dL The illness of (6.94mmol/L).The standard operation of blood glucose value being measured as in general medical analysis.If carrying out glucose tolerance examination It tests, then the blood-sugar content of diabetic will be more than to absorb 2 hours every deciliter of blood plasma 200mg grapes after 75g glucose on an empty stomach Sugared (11.1mmol/l).In dextrose tolerance test, 75g grapes are given to patient to be measured is oral after empty stomach 10-12 hours Sugar, and 1 hour and 2 hour record blood-sugar contents before it will absorb glucose and after intake glucose.In healthy individuals In, the blood-sugar content before absorbing glucose will be every deciliter of blood plasma 60mg to 110mg, absorb after glucose 1 hour, will be less than 200mg/dL, and 2 hours after intake, 140mg/dL will be less than.If 2 hours after intake, being worth for 140mg to 200mg, then this by regarding For abnormal glucose tolerance.
Term " late Type II diabetes " includes secondary drug failure, tool insulinization indication and into transforming into micro- blood Pipe and macrovascular complications (such as the patient of nephrosis or coronary heart disease (CHD).
Term " HbA1c " refers to the product of hemoglobin B chain nonenzymatic glycosylations.Its known survey of those skilled in the art It is fixed.When monitoring the treatment of diabetes, HbA1c values are even more important.Because the generation of HbA1c be substantially dependent on blood-sugar content and The service life of red blood cell, so HbA1c reflects first 4-6 weeks average blood sugar content in " blood sugar memory " meaning.HbA1c values are by sugar The sick intensive treatment of urine always well-tuned (be less than the total hemoglobin of sample 6.5%) diabetic substantially better It is protected from diabetic microangiopathies.For example, melbine itself reaches flat to the HbA1c values of diabetic It is about 1.0-1.5% to improve.In all diabetics, the reduction of this HbA1c value is not enough to reach HbA1c<6.5% and preferably <6% required target zone.
In the scope of the invention, term " insufficient glycemic control " or " insufficient glycemic control " refer to that patient shows HbA1c values higher than 6.5%, be especially more than 7.0%, it is even higher in 7.5%, the case where being especially more than 8%.
" metabolic syndrome ", also known as " X syndrome " (use) in dysbolism, and also known as " metabolism is bad comprehensive Simulator sickness " is mainly characterized by syndrome (Laaksonen DE et al., Am the J Epidemiol2002 of insulin resistance;156: 1070-7).According to ATP III/NCEP guilding principles (Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP)Expert Panel on Detection, Evaluation,and Treatment of High Blood Cholesterol in Adults(Adult Treatment Panel III)JAMA:Journal of the American Medical Association(2001)285:2486- 2497), when there are three or more following risk factors, it is diagnosed as metabolic syndrome：
1. abdominal obesity is defined as male's waistline>40 inches or 102cm and women waistline>35 inches or 94cm； Or for Japanese race or Japanese patients, it is defined as male's waistline >=85cm and women waistline >=90cm；
2. triglycerides：≥150mg/dL
3. male's HDL- cholesterol<40mg/dL
4. blood pressure >=130/85mm Hg (SBP >=130 or DBP >=85)
5. fasting blood-glucose >=100mg/dL
Have verified that NCEP defines (Laaksonen DE et al., Am J Epidemiol. (2002) 156:1070-7).May be used also By in medical analysis and such as Thomas L (eds.)：“Labor und Diagnose”,TH-Books Standard method described in Verlagsgesellschaft mbH, Frankfurt/Main, 2000 measures the glycerine three in blood Ester and HDL cholesterol.
It is diagnosed according to common definition if systolic pressure (SBP) is more than 140mm Hg and diastolic pressure (DBP) is more than 90mm Hg For hypertension.If patient suffers from overt diabetes (manifest diabetes), it is presently recommended that systolic pressure is brought down below 130mm Hg and diastolic pressure are brought down below the degree of 80mm Hg.
Term " treatment " includes the patient that therapeutic treatment has developed the illness, the especially illness of dominant form.It is therapeutic Processing can be mitigate specific adaptations disease symptom symptomatic treatment, reverse or part reverse indication situation or stopping or Slow down the causal processing of progression of disease.Therefore, the present composition and dosage form and method can be used as example through a period of time Therapeutic treatment and extended regimen.
Term " preventative process " and " prevention " are used interchangeably, and include wind of the processing in development illness described above Patient in danger, to reduce the risk.
Term " therapeutically effective amount " as used herein refers to realizing that required treatment is rung in mammalian subject or patient The amount or dosage of the active pharmaceutical ingredients of (such as reduce blood-sugar content, reduce HbA1c or losing weight) are answered, but the dosage is preferred Hypoglycemia is not caused in individual or patient.The case where pharmaceutical composition or pharmaceutical dosage form include two kinds of active pharmaceutical ingredients Under, term " therapeutically effective amount " as used herein refers to realizing that required treatment responds (example in mammalian subject or patient Such as reduce blood-sugar content, reduce HbA1c or losing weight) each active pharmaceutical ingredients combine the amounts of another active pharmaceutical ingredients Or dosage, but the dosage does not preferably cause hypoglycemia in individual or patient.
Term " tablet " includes the tablet of no coating and the tablet with one or more layers coating.In addition, term " tablet " Including with 1,2,3 layer or the even more tablet of multilayer and pressed coated tablet, wherein above-mentioned all types of tablet can be without coating Or with one or more layers coating.Term " tablet " also includes micro-tablet (mini), molten sheet (melt), chewable tablets, effervescent tablet And oral disnitegration tablet.
Term " pharmacopeia " refers to standard compendial, such as " USP31-NF26through Second Supplement " (United States Pharmacopeial Convention) or " European Pharmacopoeia6.3 " (European Directorate for the Quality of Medicines and Health Care,2000- 2009)。
Description of the drawings
Fig. 1 shows the X-ray powder diffraction figure of the crystal form (I.3X) of compound (I.3).
Fig. 2 shows the heat analysis of the crystal form (I.3X) of compound (I.3) and the determination through DSC fusing points.
Fig. 3 is shown in four groups of different ZDF rats after progress glucose stimulation, is calculated reactivity glucose AUC and is determined The glucose oscillation of amount, these rats receive control, BI 1356 (compound A), compound (I.3) (compound B) or profit and draw Arrange the combination (combining A+B) in spit of fland and compound (I.3).
Fig. 4 shows the piece for the embodiment 4 and embodiment 6 that wherein API 1 is compound (I.3) and API 2 is BI 1356 The dissolution characteristic of agent.
Fig. 5 shows that the dissolution of the tablet for the embodiment 8 that wherein API 1 is compound (I.3) and API 2 is BI 1356 is special Property.
Detailed description of the invention
The aspect (especially pharmaceutical composition, pharmaceutical dosage form, method and purposes) of the present invention is related to BI 1356 and context The benzene derivative of the glucopyranosyl substitution of definition.
Term " BI 1356 " as used herein refers to BI 1356 and its pharmaceutically acceptable salt, including its hydration Object and solvate and its crystal form.Crystal form is disclosed in WO 2007/128721.It is preferred that crystal form is polymorphic A as described herein And B.The method for preparing BI 1356 is disclosed in such as patent application WO 2004/018468 and WO 2006/048427.Li La Row spit of fland is different from comparable DPP IV inhibitor in structure, because when the benzenesulfonamide derivative of the glucopyranosyl of itself and the present invention substitution When object is applied in combination, merge particular utility and long-acting and advantageous pharmacological property, receptor-selective and advantageous pair It acts on overview or generates unexpected treatment advantage or improvement.
The benzene derivative of glucopyranosyl substitution is defined by formula (I),
Wherein R1Indicate chlorine or methyl；And R3Indicate ethyl, acetenyl, ethyoxyl, (R)-tetrahydrofuran -3- bases oxygroup or (S)-tetrahydrofuran -3- base oxygroups；Or its prodrug.
Formula (I) compound and its synthetic method are disclosed in for example following patent application：WO2005/092877、WO 2006/117360、WO 2006/117359、WO 2006/120208、WO2006/064033、WO 2007/028814、WO 2007/031548、WO 2008/049923。
In the benzene derivative of formula above (I) glucopyranosyl substitution, preferably following substituent group definition.
R1It is preferred that indicating chlorine.
R3It is preferred that indicating acetenyl, (R)-tetrahydrofuran -3- bases oxygroup or (S)-tetrahydrofuran -3- base oxygroups.
R3Most preferably indicate (R)-tetrahydrofuran -3- bases oxygroup or (S)-tetrahydrofuran -3- base oxygroups.
The benzene derivative of preferred formula (I) glucopyranosyl substitution is selected from compound (I.1) to (I.5)：
The benzene derivative of even more preferably formula (I) glucopyranosyl substitution is selected from compound (I.2) and (I.3).
According to the present invention, it should be understood that the definition of the benzene derivative of formula (I) glucopyranosyl substitution listed above is also Including its hydrate, solvate and its polymorphic and its prodrug.About preferred compound (I.1), advantageous crystal form is disclosed in In international patent application WO2007/028814, by it to be incorporated herein by reference.About preferred compound (I.2), have The crystal form of profit is disclosed in international patent application WO2006/117360, by it to be incorporated herein by reference.About preferred Compound (I.3), advantageous crystal form are disclosed in international patent application WO2006/117359, by it to be incorporated herein work in full For reference.About preferred compound (I.5), advantageous crystal form is disclosed in international patent application WO2008/049923, by its with It is incorporated herein by reference.These crystal forms have good solubility properties, assign the benzene of glucopyranosyl substitution The good bioavilability of derivative.Stablize in addition, the crystal form is physical chemistry, therefore the good storage of pharmaceutical composition is provided Deposit phase stability.
The preferred crystal form of compound (I.3) (I.3X) be characterized in that being included in 18.84,20.36 and 25.21 degree of 2 θ (± 0.1 degree of 2 θ) at peak X-ray powder diffraction figure, wherein the X-ray powder diffraction figure (XRPD) use CuKα1It radiates It arrives.
Specifically, which is included in 14.69,18.84,19.16,19.50,20.36 and 25.21 degree 2 There is peak, the wherein X-ray powder diffraction figure to use CuK at θ (± 0.1 degree of 2 θ)α1Radiation obtains.
Specifically, the X-ray powder diffraction figure be included in 14.69,17.95,18.43,18.84,19.16,19.50, 20.36, there is peak, the wherein x-ray powder to spread out at 22.71,23.44,24.81,25.21 and 25.65 degree of 2 θ (± 0.1 degree of 2 θ) It penetrates figure and uses CuKα1Radiation obtains.
More specifically, (I.3X) crystal form is characterized in that using CuKα1Obtained X-ray powder diffraction figure is radiated, which penetrates Line powder diagram is included in the peak at 2 θ of degree contained by table 1 (± 0.1 degree of 2 θ).
Table 1：The X-ray powder diffraction figure (only listing the peak that 2 θ are at most 30 °) of crystal form (I.3X)：
Even more specifically, (I.3X) crystal form is characterized in that using CuKα1Obtained X-ray powder diffraction figure is radiated, it should X-ray powder diffraction figure is included in the peak at 2 θ of degree shown in FIG. 1 (± 0.1 degree of 2 θ).
In addition, (I.3X) crystal form is characterized in that fusing point is about 149 DEG C ± 3 DEG C and (is determined through DSC；It is assessed with initial temperature； The rate of heat addition is 10K/ minutes).Obtained DSC curve is shown in Fig. 2.
Within the scope of the present invention, X-ray powder diffraction figure is recorded using the STOE-STADI P diffractometers of conduction mode, it should Diffractometer is equipped with position sensitive detectors (OED) and Cu anodes as x-ray source (CuKα1Radiation, 40kV, 40mA).In upper table 1, value " 2 θ [°] " indicates the angle of diffraction in terms of spending, and is worth " dIndicate withThe interplanar of meter Away from.Intensity shown in FIG. 1 is indicated with unit cps (counting per second).
In order to allow experimental error, it is considered that above-mentioned 2 θ values are accurate to ± 0.1 degree of 2 θ, especially ± 0.05 degree of 2 θ.That is, when commenting When whether the given crystal prototype for determining compound (I.3) is the crystal form of the present invention, if 2 θ values of the sample observed by experimentally In ± 0.1 degree of 2 θ of characteristic value described above, if being especially considered as identical in ± 0.05 degree of 2 θ of this feature value.
By DSC (differential scanning calorimetry) fusing point is determined using DSC821 (Mettler Toledo).
About active pharmaceutical ingredients, it is possible to find the Dissolution behaviours of pharmaceutical composition and dosage form and the therefore biology of active ingredient Availability is especially influenced by the particle size and its distribution of each active pharmaceutical ingredients.Pharmaceutical composition in the present invention and drug agent In type, the size distribution of active pharmaceutical ingredients is preferably so that the granularity of at least 90% each active pharmaceutical ingredients particle is less than 200 μm, i.e. X90<200 μm (in terms of volume distributions).
Specifically, in the pharmaceutical composition and pharmaceutical dosage form of the present invention, the granularity point of BI 1356 (such as its crystal form) Cloth (by volume) preferably so that at least 90% each active pharmaceutical ingredients granularity be less than 200 μm, i.e. X90<It is 200 μm, more excellent Select X90≤150 μm.Size distribution more preferably makes X90≤100 μm, even more preferably X90≤75 μm.In addition, size distribution is excellent Choosing is so that X90>0.1 μm, more preferable X90 >=1 μm, most preferably X90 >=5 μm.It is therefore preferable that size distribution makes 0.1 μm<X90< 200 μm, especially 0.1 μm<X90≤150 μm, more preferable 1 μm≤X90≤150 μm, even more preferably 5 μm≤X90≤100 μm.Profit The preferred embodiment of the size distribution of La Lieting makes X90≤50 μm or 10 μm≤X90≤50 μm.
In addition, in the pharmaceutical composition and pharmaceutical dosage form of the present invention, the size distribution of BI 1356 (such as its crystal form) (by volume) preferably so that X50≤90 μm, more preferable X50≤75 μm, even more preferably X50≤50 μm, most preferably X50≤40 μm.In addition, size distribution is preferably so that X50 >=0.1 μm, more preferable X50 >=0.5 μm, even more preferably X50 >=4 μm.Therefore, Preferred size, which is distributed, makes 0.1 μm≤X50≤90 μm, especially 0.5 μm≤X50≤75 μm, more preferable 4 μm≤X50≤75 μm, very To more preferable 4 μm≤X50≤50 μm.Preferred embodiment is 8 μm≤X50≤40 μm.
In addition, in the pharmaceutical composition and pharmaceutical dosage form of the present invention, the size distribution of BI 1356 (such as its crystal form) (by volume) preferably so that X10 >=0.05 μm, more preferable X10 >=0.1 μm, even more preferably X10 >=0.5 μm.
Specifically, about the benzene derivative of formula (I) glucopyranosyl substitution, especially compound (I.3), astoundingly It was found that undersized can influence productibility, such as by adhering to or forming a film.On the other hand, particle crosses conference and negatively affects medicine Therefore compositions and the Dissolution behaviours of dosage form negatively affect bioavilability.The preferred scope of size distribution disclosed below.
In the pharmaceutical composition and pharmaceutical dosage form of the present invention, the benzene derivative, especially of formula (I) glucopyranosyl substitution The size distribution (by volume) of compound (I.3) (such as its crystal form (I.3X)) preferably so that at least 90% each active drug The granularity of object composition is less than 200 μm, i.e. X90<200 μm, preferably X90≤150 μm.Size distribution more preferably makes the μ of X90≤100 M, even more preferably X90≤90 μm.In addition, size distribution is preferably so that X90 >=1 μm, more preferable X90 >=5 μm, even more preferably X90≥10μm.It is therefore preferable that size distribution makes 1 μm≤X90<200 μm, especially 1 μm≤X90≤150 μm, more preferable 5 μm≤ X90≤150 μm, even more preferably 5 μm≤X90≤100 μm, even more preferably 10 μm≤X90≤100 μm.Preferred embodiment is X90 ≤75μm.Another preferred embodiment is 20 μm≤X90≤50 μm.
In addition, in the pharmaceutical composition and pharmaceutical dosage form of the present invention, the benzenesulfonamide derivative of formula (I) glucopyranosyl substitution The size distribution (by volume) of object, especially compound (I.3) (such as its crystal form (I.3X)) is preferably so that X50≤90 μm, more It is preferred that X50≤75 μm, even more preferably X50≤50 μm, most preferably X50≤40 μm.In addition, size distribution is preferably so that X50 >=1 μm, more preferable X50 >=5 μm, even more preferably X50 >=8 μm.It is therefore preferable that size distribution makes 1 μm≤X50≤90 μm, especially 1 μm≤X50≤75 μm, more preferable 5 μm≤X50≤75 μm, even more preferably 5 μm≤X50≤50 μm.Preferred embodiment be 8 μm≤ X50≤40μm。
In addition, in the pharmaceutical composition and pharmaceutical dosage form of the present invention, the benzenesulfonamide derivative of formula (I) glucopyranosyl substitution The size distribution (by volume) of object, especially compound (I.3) (such as its crystal form (I.3X)) is preferably so that X10 >=0.1 μm, more It is preferred that X10 >=0.5 μm, even more preferably X10 >=1 μm.
Therefore, pharmaceutical composition of the invention or pharmaceutical dosage form be preferably characterized in that above-mentioned designated size distribution X90, One in X50 and/or X10 or following implementation：
Value X90 refers to 90% volume distribution values measured using laser-diffractometer.In other words, for purposes of the present invention, The expression of X90 values is distributed according to volume, the granularity that the particle of 90% amount is less than.Similarly, value X50 refers to using laser diffraction 50% volume distribution values (intermediate value) that instrument measures.In other words, for purposes of the present invention, X50 values expression is distributed according to volume, The granularity that the particle of 50% amount is less than.Similarly, value X10 refers to being distributed using 10% volume that laser-diffractometer measures Value.In other words, for purposes of the present invention, X10 values expression is distributed according to volume, the granularity that the particle of 10% amount is less than.
Preferably, all X90, X50, X10 values of context are by volume and by laser diffractometry (especially low-angle laser Scattering, i.e. Fraunhofer diffraction) it measures.Preferred test is disclosed in experimental section.Volume of the laser diffractometry to particle Sensitive and offer volume average particle sizes are equal to weight average particle size if density constant.One kind known to those skilled in the art Particle size distribution result obtained by technology can be related to the result obtained by another technology, such as experiential routine experiment. Alternatively, the granularity point in pharmaceutical composition or dosage form can be measured by microscopy (especially electron microscopy or scanning electron microscopy) Cloth.
In order to provide the suitable initial substance being made of active pharmaceutical ingredients, grinding (such as jet grinding (jet- Milled) or needle grinds (pin-milled)) such as BI 1356 or benzene derivative (the especially compound of glucopyranosyl substitution (I.3) and its crystal form (I.3X)).
Hereinafter, preferred excipient and carrier in the pharmaceutical composition of the present invention are described in further detail.Excipient It is preferably pharmaceutically acceptable.
Preferably, excipient is selected so that it is compatible with BI 1356, i.e., so that being not present in pharmaceutical composition or only depositing It degrades in the BI 1356 of bottom line.Degradation can be tested in standard testing, such as is stored under 40 DEG C and 75% relative humidity It is tested after 6 months.In this case, term " degradation (marginal degradation) of bottom line " should refer to Li Lalie The chemical degradation in spit of fland is less than 5 weight %, preferably smaller than 3 weight %, the even more preferably less than BI 1356 of 2 weight %.It can be by known Analytic approach (such as using HPLC or UV methods) measures content and corresponding degradation.
In the pharmaceutical composition of the present invention, excipient preferably comprises one or more diluents.
In addition, in the pharmaceutical composition of the present invention, excipient preferably comprises one or more diluents and one kind or more Kind adhesive.
In addition, in the pharmaceutical composition of the present invention, excipient preferably comprises one or more diluents and one kind or more Kind adhesive and one or more disintegrants and optional other compositions.
In addition, in the pharmaceutical composition of the present invention, excipient even more preferably includes one or more diluents and one Kind or a variety of adhesives and one or more disintegrants and one or more lubricants and optional other compositions.
Some excipient can have the function of two or more simultaneously, such as may act as diluent and adhesive, or serve as viscous Mixture and disintegrant, or serve as diluent, adhesive and disintegrant.
When the amount of active pharmaceutical ingredients is smaller, one or more diluents (another term is known as filler) are added, because The official minimum tablet weight (such as 100mg or 100mg or more) of this realization and satisfactorily content uniformity (such as Standard deviation<3%).Observe that the common diluents and BI 1356 of such as lactose, sucrose and microcrystalline cellulose are incompatible.
One or more diluents of pharmaceutical composition suitable for the present invention are preferably selected from：Cellulose (especially cellulose powder End), calcium monohydrogen phosphate (especially calcium phosphate dibasic anhydrous or calcium phosphate dibasic dihydrate), erythritol, mannitol, starch, pregelatinization Starch and xylitol include the derivative and hydrate of above-mentioned substance.Diluent pregelatinized starch shows additional adhesive Matter.In diluent listed above, mannitol and pregelatinized starch are particularly preferred.
In the case of the pharmaceutical composition of the present invention includes a kind of diluent, then diluent is preferably mannitol or pre- Gelatinized starch, most preferably mannitol.
In the case of the pharmaceutical composition of the present invention includes two or more diluents, then the first diluent is preferably sweet Reveal sugar alcohol and the second diluent is selected from diluent described above, even more preferably shows the pre- glue of additional adhesive properties Solidifying starch.
Mannitol described in context is preferably adapted to the small grain size grade of granulation.Example is PearlitolTM50C (Roquette)。
Pregelatinized starch described in context can be any commercially available grade.Example is Starch1500TM(Colorcon)。
The pharmaceutical composition of the present invention does not preferably include substance selected from the following：Glucose, fructose, sucrose, lactose and wheat Bud dextrin, especially lactose.It is preferred that the amount for the above-mentioned substance (especially lactose) for being included is no more than 2 weight % of total composition, even More preferably contained amount is no more than 0.5 weight % of total composition.
One or more adhesives in pharmaceutical composition provide pharmaceutical composition (such as during granulation) and compressed tablets The adhesiveness of agent.It increases existing cohesive strength in diluent.Observe that for example, sucrose and the common of microcrystalline cellulose glue Mixture is incompatible with BI 1356.
The adhesive of one or more pharmaceutical compositions for being suitable for the present invention is preferably selected from：Copolyvidone (copovidone), hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC) and polyvinylpyrrolidone, pregelatinization Starch and low substituted hydroxypropyl cellulose (L-HPC), include the derivative and hydrate of substance described above.Even more preferably Adhesive be copolyvidone and/or pregelatinized starch.
Copolyvidone described in context is preferably the copolymer of vinyl pyrrolidone and vinyl acetate, molecular weight Preferably from about 45000 to about 70000.Example is KollidonTMVA64(BASF)。
Hydroxypropyl methyl cellulose (also known as HPMC or hydroxypropyl methylcellulose) described in context is preferably that hydroxypropyl first is fine Dimension element 2910.The viscosity of hydroxypropyl methyl cellulose is preferably within the scope of about 4cps to about 6cps.Example is MethocelTME5Prem LV(Dow Chemicals)。
The range of viscosities of hydroxypropyl cellulose (also known as HPC) described in context is preferably in about 300mPas to about Within the scope of 600mPas.The molecular weight of hydroxypropyl cellulose is preferably from about 60000 to about 100000, and for example, about 80000.It is real Example is KlucelTMEF(Aqualon)。
Polyvinylpyrrolidone (also known as PVP, povidone (polyvidone or povidone)) described in context Molecular weight is preferably from about 28000 to about 54000.The range of viscosities of polyvinylpyrrolidone is preferably from about 3.5mPas to about 8.5mPa·s.Example is KollidonTM25 or KollidonTM30(BASF)。
The hydroxypropyl content of low substituted hydroxypropyl cellulose (also known as L-HPC) described in context is preferably in about 5 weights It measures within the scope of % to about 16 weight %.
Adhesive pregelatinized starch described above and L-HPC show additional diluent and disintegrant property, and may be used also As the second diluent or disintegrant.
One or more disintegrants are used to help divide pharmaceutical composition and dosage form after administration.It observes for example, micro- The common disintegrant of crystalline cellulose is incompatible with BI 1356.
One or more disintegrants of pharmaceutical composition suitable for the present invention are preferably selected from：Crospovidone, low substituted hydroxyl Propyl cellulose (L-HPC) and starch (such as native starch, especially cornstarch and pregelatinized starch), including above-mentioned substance Derivative and hydrate.In above-mentioned disintegrant, cornstarch, pregelatinized starch and Crospovidone are even more preferably.
Astoundingly, it has been found that if the benzene derivative that BI 1356 replaces with formula (I) glucopyranosyl is combined in It (is especially combined in a dosage form, such as tablet or capsule) in the pharmaceutical composition of the present invention, then preferably at least two kinds disintegrations Agent.It is preferred that disintegrant is cornstarch and Crospovidone.
If BI 1356 and the benzene derivative inhibitor of formula (I) glucopyranosyl substitution are combined in the medicine group of the present invention It closes and (is especially combined in a dosage form, such as tablet or capsule) in object, then the combination of even more desirably at least three kinds disintegrants. It is preferred that disintegrant is cornstarch, pregelatinized starch and Crospovidone.
Crospovidone described in context is preferably insoluble povidone, i.e. the cross-linked form of PVP.Example is KollidonTMCL or KollidonTMCL-SF(BASF)。
Cornstarch described in context is preferably native starch.Example is cornstarch (Maize starch) (extra white) (Roquette)。
Above-mentioned disintegrant starch and pregelatinized starch show additional diluent property, therefore it is dilute to also act as such as second Release agent.
One or more lubricants in pharmaceutical composition reduce in prepared by tablet (i.e. during compacting and ejection cycle) Friction.In addition, its help prevents tablet material from being adhered to punch die and press machine.
The pharmaceutical composition of the present invention preferably also includes one or more lubricants.Suitable for pharmaceutical composition of the invention One or more lubricants are preferably selected from：(especially molecular weight is about 4400 for talcum powder (such as from Luzenac), polyethylene glycol Polyethylene glycol to about 9000 ranges), rilanit special, aliphatic acid and fatty acid salt (in particular its calcium salt, magnesium salts, sodium salt Or sylvite, such as behenic acid calcium (calcium behenate), calcium stearate, sodium stearyl fumarate or magnesium stearate (such as (such asMallinckrodt orPeter Greven).More preferable lubricant is tristearin Sour magnesium and talcum powder.
Astoundingly, it has been found that if the benzene derivative that BI 1356 replaces with formula (I) glucopyranosyl is combined in It (is especially combined in a dosage form, such as tablet or capsule) in the pharmaceutical composition of the present invention, then preferably at least two kinds lubrications Agent.Preferred emollient is talcum powder and magnesium stearate.The combination of two or more lubricants assigns low knockout press, and for example in piece Agent avoids final mixture from adhering in preparing.
One or more glidants are the reagent for the powder flowbility for improving pharmaceutical composition.
The pharmaceutical composition of the present invention also may include one or more glidants.One suitable for pharmaceutical composition of the invention Kind or a variety of glidants are preferably selected from：Talcum powder and colloidal silicon dioxide (such as AerosilTM200Pharma(Evonik))。
The granularity of excipient (especially one or more diluents, such as mannitol) is preferably in 1 to 500 μ m. Granularity in granulation step is preferably 25 to 160 μm.Granularity in direct tablet compressing technique is preferably 180 to 500 μm.Granularity is preferred Pass through sieve analysis.The particle of preferably at least 80 weight %, more preferably at least 90 weight %, most preferably at least 95 weight % are set In range.
According to the first embodiment of the invention, pharmaceutical composition only includes a kind of active pharmaceutical ingredients, i.e. BI 1356.
The preferred composition of first embodiment of the invention includes diluent, adhesive and disintegrant.The composition is preferred It only include a kind of diluent.The composition even more preferably includes only a kind of diluent and only a kind of adhesive.The composition is very To more preferably comprising only a kind of diluent, only a kind of adhesive and only a kind of disintegrant.Composition also may include at least one profit Lubrication prescription.In addition, composition also may include at least one glidant.
The pharmaceutical composition of first embodiment preferably comprises
Wherein percentage is the weight percent of total composition.
Following range is even more preferably：
Wherein percentage is the weight percent of total composition.
Another pharmaceutical composition of first embodiment preferably comprises
Wherein percentage is the weight percent of total composition.
Following range is even more preferably：
Wherein percentage is the weight percent of total composition.
In aforementioned pharmaceutical compositions, preferred diluent is mannitol.It is preferred that adhesive is copolyvidone.It is preferred that being disintegrated Agent is cornstarch.Preferred emollient is magnesium stearate.In the case of pharmaceutical composition includes the second diluent, preferably pre- glue Solidifying starch.It is with additional adhesive properties.
The pharmaceutical dosage form (such as tablet or capsule) prepared with the pharmaceutical composition of first embodiment contains preferred therapeutic A effective amount of BI 1356 is as active ingredient.Preferred dose ranging from 0.1 to 100mg, more preferably 0.5 to 20mg, even More preferably 1 to 10mg.Preferred dose is such as 0.5mg, 1mg, 2.5mg, 5mg and 10mg.
Second embodiment of the invention, pharmaceutical composition include two kinds of active pharmaceutical ingredients, i.e., BI 1356 and The benzene derivative of formula (I) glucopyranosyl substitution of contextual definition, especially BI 1356 and compound (I.3).
Astoundingly, the benzene derivative (especially compound (I.3)) of formula (I) glucopyranosyl substitution can be observed to the greatest extent Pipe has the glucopyranosyl moiety containing free hydroxyl group, but still compatible with BI 1356, i.e., BI 1356 combines glucopyra The benzene derivative of glycosyl substitution does not show or only shows the degradation of bottom line.
The preferred pharmaceutical compositions of second embodiment include that BI 1356 and compound (I.3) are used as two kinds of active medicines Composition.Pharmaceutical composition or dosage form preferably comprise BI 1356 and compound (I.3), the wherein at least compound of 50 weight % (I.3) it is in its crystal form (I.3X) form as defined above.In the pharmaceutical composition or dosage form, more preferably at least 80 weight %, Even more desirably at least the compound (I.3) of 90 weight % is in its crystal form (I.3X) form as defined above.Pharmaceutical composition or Dosage form preferably comprise in one or more crystal forms (especially polymorphic A and B) BI 1356 (such as WO2007/128721 (and by its with It is hereby incorporated by reference) described).
The preferred pharmaceutical compositions of second embodiment of the invention include one or more diluents, one or more bondings Agent and one or more disintegrants.The even more preferably pharmaceutical composition of second embodiment of the invention includes one or more Diluent, one or more adhesives, one or more disintegrants and one or more lubricants.The composition preferably comprises one Kind or two kinds of diluents.The composition even more preferably includes one or two kinds of diluents and a kind of adhesive.The composition is very To more preferably comprising one or two kinds of diluents, a kind of adhesive and a kind of disintegrant.The composition even more preferably includes one Kind or two kinds of diluents, a kind of adhesive and at least two disintegrants.The composition even more preferably includes one or two kinds of dilute Release agent, one or two kinds of adhesives and at least two disintegrants.The composition even more preferably include one or two kinds of diluents, One or two kinds of adhesives, at least two disintegrants and a kind of lubricant.The composition even more preferably includes one or two Diluent, one or two kinds of adhesives, at least two disintegrants and one or two kinds of lubricants.The composition is even more preferably wrapped Containing one or two kinds of diluents, one or two kinds of adhesives, at least two disintegrants and two kinds of lubricants.The composition is even more Preferably comprise one or two kinds of diluents, one or two kinds of adhesives, three kinds of disintegrants and two kinds of lubricants.In addition, composition It also may include at least one glidant.Upper and lower preferred diluent, adhesive, disintegrant, lubricant and glidant disclosed herein.
The pharmaceutical composition of second embodiment preferably comprises
Wherein percentage is the weight percent of total composition.
Following range is even more preferably：
Wherein percentage is the weight percent of total composition.
In addition, the pharmaceutical composition may include the profit within the scope of 0.1-15% in terms of one or more weight by total composition Lubrication prescription.
The pharmaceutical composition of second embodiment preferably comprises
Wherein percentage is the weight percent of total composition.
In aforementioned pharmaceutical compositions, preferred diluent is mannitol, and preferably adhesive is copolyvidone and preferably collapses It solves agent and is selected from cornstarch and Crospovidone.Preferred emollient is selected from magnesium stearate and talcum powder.Include the in pharmaceutical composition In the case of two diluents, preferred pregelatinized starch.Pregelatinized starch has additional adhesive and disintegrant property.
Therefore, the preferred pharmaceutical compositions of second embodiment are characterized in that consisting of：
Wherein percentage is the weight percent of total composition.
Another preferred pharmaceutical compositions of second embodiment are characterized in that consisting of：
Wherein percentage is the weight percent of total composition.
Aforementioned pharmaceutical compositions preferably additionally comprise lubricant.Lubricant is preferably the 0.5-2% in terms of the weight of total composition Amount magnesium stearate.
Aforementioned pharmaceutical compositions preferably additionally comprise at least two lubricants.First lubricant is preferably with total composition The magnesium stearate of the amount of weight meter 0.5-2%.Second lubricant is preferably the cunning of the amount of the 0.5-10% in terms of the weight of total composition Mountain flour.
Therefore, the preferred pharmaceutical compositions of second embodiment are characterized in that consisting of：
Wherein percentage is the weight percent of total composition.
Another preferred pharmaceutical compositions of second embodiment are characterized in that consisting of：
Wherein percentage is the weight percent of total composition.
The pharmaceutical composition of the present invention also may include one or more taste masking agent (taste masking agent) (such as sweetener or flavoring agent) and pigment.
The pharmaceutical composition of the present invention also may include one or more layers coating.Preferably non-functional coatings.
The pharmaceutical composition of the present invention is preferably solid composite medicament, is especially intended for oral medication person.Including this The pharmaceutical dosage form of the present invention of the pharmaceutical composition of invention is preferably solid pharmaceutical dosage formulation, particularly for oral medication person.Example is Capsule, tablet (such as thin membrane coated tablet) or granule.
The pharmaceutical dosage form (such as capsule or tablet) of first embodiment of the invention only includes a kind of active pharmaceutical ingredients, i.e., BI 1356.
The pharmaceutical dosage form (such as capsule or tablet) of second embodiment of the invention includes two kinds of active pharmaceutical ingredients, i.e., sharp The benzene derivative of formula (I) glucopyranosyl of La Lieting and contextual definition substitution, especially BI 1356 and compound (I.3).Tablet can be individual layer tablet, and two of which active pharmaceutical ingredients are present in the single layer.Alternatively, tablet can be double-layer tablets Agent, one kind in two of which active pharmaceutical ingredients is present in first layer, and another active pharmaceutical ingredients are present in the second layer In.Alternatively, preparation can be thin membrane coated tablet, one kind in two of which active pharmaceutical ingredients is present in label, and another work Property pharmaceutical compositions are present in based calcium.Alternatively, tablet can be tri-layer tablets, wherein it is each only contain a kind of active medicine at Two layers of part is separated by the third layer without any active pharmaceutical ingredients.Alternatively, tablet can be pressed coated tablet, i.e., a kind of work Property pharmaceutical compositions contained in for example a diameter of 2-6mm tabloid in and another active pharmaceutical ingredients be contained in the second particle or mixture In and be pressed into a tabloid tablet of a big pressed coated tablet.All types of above-mentioned tablets without coating or can have There are one or more layers coating, especially film coating.Preferably non-functional coatings.
It should be appreciated that being intended to give to patient and needing one or more present invention to be used in the present invention treats or prevents The amount of active pharmaceutical ingredients by with administration route, need the property and severity, patient age, body of the illness that treat or prevent Weight and physical condition, Concomitant medications and change, and will finally be determined by attending physician.It is preferable, however, that amount is general so that by giving The glycemic control of patient to be treated can be improved by giving pharmaceutical dosage form.
The benzenesulfonamide derivative for BI 1356 and the glucopyranosyl substitution to be used in pharmaceutical dosage form of the present invention described in hereafter The preferred scope of the amount of object.These ranges refer to being given once daily for adult patient (people that especially such as weight is about 70kg) Amount and can be according to 2,3,4 times or 4 times or more and other administration routes being given once daily and patient age is accordingly adjusted.Dosage And the range of amount is calculated for the active part of difference.
The preferred agents dosage form of second embodiment contains the BI 1356 of therapeutically effective amount and the pyrans of therapeutically effective amount The benzene derivative (especially compound (I.3)) of glucosyl group substitution.Ranging from the 0.1 to 30mg of the preferred amounts of BI 1356, it is excellent Select 0.5 to 20mg, even more preferably 1 to 10mg, most preferably 2 to 5mg.Preferred dose is such as 0.5mg, 1mg, 2.5mg, 5mg And 10mg.Glucopyranosyl substitution benzene derivative (especially compound (I.3)) preferred amounts ranging from 0.5 to 100mg, It is preferred that 0.5 to 50mg, even more preferably 1 to 25mg, even more preferably 5 to 25mg, most preferably 10 to 25mg.Glucopyranosyl The preferred dose of substituted benzene derivative be such as 1mg, 2mg, 2.5mg, 5mg, 7.5mg, 10mg, 12.5mg, 15mg, 20mg, 25mg and 50mg.The pharmaceutical dosage form of second embodiment contains the dosage combination for example selected from embodiment described in following table：
Tablets can be thin membrane coated tablet.Film coating usually accounts for the 2-5 weight % of total composition, and preferably comprises Film forming agent, plasticizer, glidant and optional one or more pigments.Illustrative coated composition may include hydroxypropyl methyl fibre Dimension plain (HPMC), polyethylene glycol (PEG), talcum powder, titanium dioxide and optional iron oxide, including iron oxide red and/or oxidation Iron oxide yellow.Illustrative coated composition may include hydroxypropyl methyl cellulose (HPMC), polyethylene glycol (PEG), talcum powder, titanium dioxide Titanium, mannitol and optional iron oxide, including iron oxide red and/or iron oxide yellow.
The Dissolution behaviours of pharmaceutical dosage form of the present invention are preferably so that after 45 mins, for one or two kinds of medicament active compositions Each of, each medicament active composition dissolving of at least 75 weight %, even more desirably at least 90 weight %.More preferably one In embodiment, after 30 minutes, for each of one or two kinds of medicament active compositions, at least 75 weight %, even more Each medicament active composition of preferably at least 90 weight % dissolves.In a most preferred embodiment, over the course of 15 mins, for one Each drug of each of kind or two kinds of medicament active compositions, at least 75 weight %, even more desirably at least 90 weight % is lived Sexual element dissolves.Dissolution behaviours, such as USP31-NF26S2 can be measured in standard dissolves out test, the 711st chapter (dissolution rate) Described in pharmacopeia.Preferred test is disclosed in experimental section.
The disintegration property of pharmaceutical dosage form of the present invention preferably so that in 40 minutes, more preferably in 30 minutes, it is even more excellent It is selected in 20 minutes, most preferably in 15 minutes, pharmaceutical dosage form disintegration.Disintegration property, example can be measured in standard disintegration test Such as USP31-NF26S2, described in the pharmacopeia of the 701st chapter (disintegration).Preferred test is disclosed in experimental section.
For each of one or two kinds of active pharmaceutical ingredients, the content uniformity of pharmaceutical dosage form of the present invention preferably compared with Height, preferably in 85 to 115 weight %, more preferably in 90 to 110 weight %, even more preferably within the scope of 95 to 105 weight %.It can Content uniformity, such as USP31-NF26S2 are measured using such as 30 kinds randomly selected pharmaceutical dosage forms in standard testing, the Described in the pharmacopeia of 905 chapters (dosage unit homogeneity).
The agent of the present invention of such as tablet, capsule or thin membrane coated tablet is prepared using method well known to those skilled in the art Type.
The preferred method for preparing tablet is that compacting is in the pharmaceutical composition (i.e. direct pressing) of powder type or compacting is in The pharmaceutical composition of particle shape formula, and when needing, suppressed together with additional excipient.
The particle of the pharmaceutical composition of the present invention is prepared using method well known to those skilled in the art.Make a kind of or more The preferred method that kind of active ingredient is pelletized together with excipient include wet granulation (such as bulk drug of pretreatment adds with interior granulation or fluid bed it is wet Method is pelletized) and dry granulation (also known as roller compacting).
In a preferred wet granulation step, granulation liquid is only solvent or solvent mixture, or is one or more viscous Preparation of the mixture in solvent or solvent mixture.Suitable adhesive is disclosed in above.Example is copolyvidone.Suitably Solvent is such as water, ethyl alcohol, methanol, isopropanol, acetone, preferably pure water, including its mixture.Solvent is that will not remain on Volatile components in final product.It is (especially one or more dilute with other excipient to be pre-mixed one or more active ingredients Agent, optional one or more adhesives and optional one or more disintegrants are released, lubricant is usually excluded), and for example make It is pelletized together with granulation liquid with high shear granulator.Generally one or more dry and screening step after wet granulation step Suddenly.Optionally inserted wet sieving step is subsequently dried particle and carries out dry screening.For example, fluidized bed drying then can be used Device is dried.
The preparation method of the present invention is preferably characterized in that following granulation step, wherein first and second active pharmaceutical ingredients with One or more diluents, one or more adhesives and one or more disintegrants are pelletized together.
The preparation method of the present invention is preferably characterized in that following at least two granulation step：Wherein in a granulation step In, the first active pharmaceutical ingredients are together with one or more diluents, one or more adhesives and one or more disintegrants Granulation, and in another granulation step, the second active pharmaceutical ingredients and one or more diluents, one or more adhesives and One or more disintegrants are pelletized together.
Preferably, in the above-mentioned methods, the particle obtained by one or more granulation steps optionally with one or more volumes Outer disintegrant mixing, and with one or more mix lubricants.
Through the particle that the screening of appropriate sieve is dry.(especially one or more disintegrants and stream is helped adding other excipient Agent and optional lubricant talcum powder exclude the lubricant of in particular magnesium stearate) after, in such as free-falling mixing machine Mixture is mixed in the suitable mixing machine of (free fall blender), then add one or more lubricants (such as Magnesium stearate), and finally mixed in mixing machine.
Therefore, the illustrative wet granulation step of particle for being used to prepare the pharmaceutical composition comprising the present invention includes
A., one or more adhesives are optionally dissolved in in environment temperature the solvent or solvent mixture of such as pure water In be made granulation liquid；
B. one or more active pharmaceutical ingredients, one or more diluents, optional are mixed in suitable mixing machine One or more adhesives and optional one or more disintegrants are to be made premix；
C. premix is soaked with granulation liquid, and then in such as high shear mixer by the premix system of wetting Grain；
D. the screen size of the premix optionally through sieve screening granulation, wherein sieve is at least 1.0mm and is preferably 3mm；
E. at about 40-75 DEG C and preferably 55-65 DEG C of entering air temperature, the dry particle in such as fluidized bed dryer Until the required loss on drying value obtained is within the scope of 1-5%；
F. for example dry particle is gone by being sieved through the sieve that screen size is 0.6mm-1.6mm, preferably 1.0mm Block；And
G. screened lubricant is preferably added into particle, finally to be mixed in cube mixing machine (cube mixer) It closes.
In another method, a part of excipient (example can be added in a manner of particle before the final mixing of step g Such as the disintegrant of one or more such as cornstarch of a part) or additional disintegrant (such as Crospovidone) and/or one Kind or plurality of diluent (such as pregelatinized starch).
In another program of method, with obtained in preparation process a to e in single kettle type high shear granulation step Grain, and it is then dry in single kettle type granulator.Therefore, an aspect of of the present present invention is related to the pharmaceutical composition comprising the present invention Particle.
The illustrative dry granulation procedure of particle for being used to prepare the pharmaceutical composition comprising the present invention includes
(1) one or two kinds of active pharmaceutical ingredients and all or part of excipient are mixed in mixing machine；
(2) in suitable roller compactor compacting step (1) mixture；
(3) by suitably grinding or the ribbon obtained during step (2) is broken into little particle by screening step；
(4) particle of mixing step (3) and remaining excipient optionally in mixing machine, obtain final mixture；
(5) it is pressed by the particle of compacting step (3) on suitable tablet press machine or the final mixture of step (4) Piece, to which label be made；
(6) non-functional coatings optionally are coated to the label of step (5).
The particle of first embodiment of the invention only includes a kind of active pharmaceutical ingredients (drug), i.e. BI 1356.
The particle of second embodiment of the invention includes two kinds of active pharmaceutical ingredients, i.e. BI 1356 and contextual definition The benzene derivative of formula (I) glucopyranosyl substitution, especially BI 1356 and compound (I.3).
The preferred size of particle is in 25 to 800 μ ms, even more preferably in 40 μm to 500 μ ms.It is preferred that passing through Screen analysis (such as sieving (sonic sifter) with sound) measures size.It is preferably at least 80 weight %, more preferably at least 90 weight %, optimal The choosing at least particle of 95 weight % is in given range.
When preparing capsule, further by described in such as above step (f.) and (g.) particle or final mixture fill out It is charged in capsule.
When preparing the capsule of second embodiment of the invention, the particle of second embodiment of the invention can be used, that is, wrap Particle containing two kinds of active pharmaceutical ingredients.Alternatively, the particle of first embodiment of the invention can be used, that is, include that BI 1356 is made It is a kind of benzene derivative of formula (I) glucopyranosyl substitution for particle of active pharmaceutical ingredients, and comprising contextual definition, outstanding The particle of its compound (I.3).
When preparing tablet or label, using appropriate tablet press machine will such as above step (g.) particle or final mixture Further it is pressed into the tablet with target tablet core weight and appropriate size and compression strength.Final mixture includes the present invention Grain and one or more lubricants and optional one or more disintegrants and optional one or more glidants.The volume Outer disintegrant is such as Crospovidone.
When preparing the individual layer tablet of second embodiment of the invention, the particle of second embodiment of the invention can be used, Include the particle of two kinds of active pharmaceutical ingredients.Alternatively, the particle of first embodiment of the invention can be used, that is, include Li Lalie Spit of fland as a kind of particle of active pharmaceutical ingredients, and comprising contextual definition formula (I) glucopyranosyl substitution benzenesulfonamide derivative The particle of object, especially compound (I.3).
When preparing the bilayer tablet of second embodiment of the invention, first embodiment of the invention can be used in first layer Particle, that is, include BI 1356 can be used as a kind of particle of active pharmaceutical ingredients, and in the second layer it is fixed comprising context The particle of the benzene derivative of formula (I) glucopyranosyl substitution of justice, especially compound (I.3).
The tablet (such as individual layer tablet) of second embodiment of the invention preferably comprises
Wherein percentage is the weight percent of total composition.
Following range is even more preferably：
Wherein percentage is the weight percent of total composition.
In addition, following excipient and range are preferred：
Wherein percentage is the weight percent of total composition.Especially in the case of realizing higher tablet weight, such as In the case of the individual layer tablet made of two kinds of particles (every layer respectively has a kind of active ingredient) described above or bilayer tablet, The additional disintegrant (such as Crospovidone) of in terms of the weight of total composition 0 to 2% amount can be used.
In addition, following excipient and range are more preferable：
Wherein percentage is the weight percent of total composition.
For the lubricant aequum for reducing in tablet, may be selected to use external lubrication system.
When preparing thin membrane coated tablet, film coating suspension is prepared and using standard film coater film coating suspension to compacting The coating of label cladding is until weight increase is about 2-5%, preferably from about 3%.Film coating solvent is that will not remain in final product Volatile components.In another embodiment, film coating may include one kind in two kinds of active pharmaceutical ingredients.
Alternatively, Tablets can be prepared by direct pressing.Suitable direct pressing method includes the following steps：
(1) one or two kinds of active ingredients are pre-mixed in mixing machine with most of excipient to obtain premix；
(2) premix is optionally screened with dry method through sieve, to detach flocculated particle and improve content uniformity；
(3) premix of mixing step (1) or (2) in mixing machine adds remaining excipient optionally into mixture And continue to mix；
(4) by the final mixture of the pressing step (3) on suitable tablet press machine by its tabletting, to which label be made；
(5) label of step (4) is optionally given to coat non-functional coatings.
Known package material (such as PVC- can be used in the pharmaceutical composition and dosage form (especially tablet or capsule) of the present invention Bubble-cap, PVDC- bubble-caps, PVC/PVDC- bubble-caps) or moisture-proof packaging material (such as aluminium foil blister packaging, aluminium/aluminium bubble-cap, it is transparent or The opaque polymer blister with medicine bag, PA tube, vial, PP bottles and HDPE bottles, optionally opened containing child-resistant Feature (child-resistant feature) is opened (such as by pressure seal mouth (press-and-twist closure) or aobvious to steal (tamper evident)) it is packed.Inner packaging material may include drier (such as molecular sieve or silica gel) to improve activity The chemical stability of drug ingedient.Opaque packaging (such as coloring blister material, pipe, Brown Glass Brown glass bottles and jars only etc.) can be by reducing light The storage period degraded for extending active pharmaceutical ingredient.Object for distribution may include being packaged in packaging material as described above In pharmaceutical composition or dosage form and label or package insert, with reference to generally including in the commercially available packaging of therapeutic products (it may include in relation to indication, usage, dosage, administration, contraindication and/or the attention thing for using the treatment product specification ).In one embodiment, label or package insert point out that the composition can be used for any purpose as described herein.
The pharmaceutical composition and pharmaceutical dosage form of the present invention is shown relative to anti-diabetic monotherapy in treatment and prevention The advantageous effect of disease and illness described in text.It can be found for example that about validity, dosage strengths, dose frequency, pharmacodynamics The advantageous effect of matter, pharmacokinetic property, less adverse reaction, convenience, compliance etc..
Compared with the monotherapy or melbine monotherapy that use independent SGLT2 inhibitor or DPP IV inhibitor, Glycemic control is significantly improved in the patient that the pharmaceutical composition and pharmaceutical dosage form of the present invention is especially described below.Glycemic control changes The increase that the kind increase for being determined as blood glucose reduction and HbA1c are reduced.For single in patient (patient especially described below) Therapy, by give be higher than specific maximum dose level drug generally cannot further significantly improve glycemic control.In addition, in view of latent Side effect, it may be undesirable to maximum dose level is used for a long time and is treated.Therefore, by using independent SLGT2 inhibitor or DPP IV inhibitor cannot be in all patients in fact using the monotherapy of another antidiabetic medicine (such as melbine) Now satisfactory glycemic control.In these patients, diabetes may continue to be in progress and be likely to occur related with diabetes Complication, such as macrovascular complications.Compared with anti-diabetic monotherapy, pharmaceutical composition of the invention and pharmaceutical dosage form with And the method for the present invention makes the HbA1c values of more patients be reduced to required target zone, such as<7% and preferably<6.5%, and it is therapeutic Processing time is longer.
The pharmaceutical composition and pharmaceutical dosage form of the present invention provides well tolerable therapy for patient and improves patient's compliance.
Monotherapy using DPP IV inhibitor is related with the insulin secreting ability of patient or insulin sensitivity.Separately On the one hand, unrelated with the insulin secreting ability of patient or insulin sensitivity by giving SGLT2 inhibitor treatment.Therefore, Any patient can benefit from hyperinsulinism content or insulin resistance and/or unrelated hyperinsulinemia to be made With the therapy of pharmaceutical composition and the pharmaceutical dosage form combination of the present invention.Because combination or replacement give SGLT2 inhibitor, this A little patients still can with hyperinsulinism content or insulin resistance or unrelated hyperinsulinemia pharmaceutical composition And pharmaceutical dosage form treatment.
By improving activity GLP-1 contents, BI 1356 of the invention can reduce the glucagons secretion of patient.Cause This, this generates limitation hepatic glucose.In addition, the high activity GLP-1 contents that BI 1356 generates will be to β cytothesises and new life Generate beneficial effect.All these features make pharmaceutical composition and pharmaceutical dosage form quite be applicable in and have important meaning in the treatment.
When the present invention refers to the patient that needs treat or prevent, the treatment and prevention of people, but pharmaceutical composition are referred mainly to Object can also mutually be applied in the veterinary science of mammal.In the scope of the invention, adult patient preferred age is 18 years old or more People.Equally in the scope of the invention, patient is teenager, i.e., the people that the age is 10 to 17 years old, preferred age is 13 to 17 years old. Think in younger population, give the pharmaceutical composition of the present invention, it is possible to find splendid HbA1c is reduced and splendid fasting blood Starching glucose reduces.Additionally it is believed that in younger population, especially in overweight and/or obese patient, notable body can be observed It reduces again.
As described above, by giving the pharmaceutical composition and pharmaceutical preparation of the present invention, and especially because wherein pyrans Portugal The high SGLT2 inhibitory activity of the benzene derivative of grape glycosyl substitution, urine discharge of the excess blood glucose through patient so that weight may not Increase or even weight loss.Therefore, treatment or prevention of the invention are advantageously adapted to need the patient of the treatment or prevention, this A little patients have one or more illnesss selected from the following after diagnosing：Overweight and obesity, especially I grade obesity, II grades of obesities Disease, III level obesity, visceral obesity and abdominal obesity.In addition, the treatment or prevention of the present invention are advantageously adapted to avoid body The increased patient of weight.
The pharmaceutical composition and pharmaceutical dosage form of the present invention shows splendid glycemic control effect, is especially reducing fasting plasma In terms of glucose, Post-prandial plasma glucose and/or glycosylated hemoglobin (HbA1c).By the pharmaceutical composition for giving the present invention Object or pharmaceutical dosage form, accessible HbA1c, which is reduced, is equal to or more than preferably 1.0%, more preferably equal to or greater than 2.0%, even more Preferably equal to or greater than 3.0%, and reduce especially in the range of 1.0% to 3.0%.
In addition, the method and/or purposes of the present invention are advantageously used in the trouble of display one kind, two or more following illnesss Person：
(a) fasting blood-glucose or serum glucose concentration are more than 100mg/dL, especially greater than 125mg/dL；
(b) Post-prandial plasma glucose is equal to or more than 140mg/dL；
(c) HbA1c values are equal to or more than 6.5%, are especially equal to or more than 7.0%, are especially equal to or more than 7.5%, even more Especially it is equal to or more than 8.0%.
Invention additionally discloses pharmaceutical compositions or pharmaceutical dosage form to suffer from type-2 diabetes mellitus or display glycosuria early period for improving Purposes in the glycemic control of the patient of first symptom of disease.Therefore, the invention also includes diabetes mellitus preventions.Therefore, if upper It states after a kind of pre-diabetes symptom occurs i.e. using pharmaceutical composition or pharmaceutical dosage form the improvement glycemic control of the present invention, then may be used Postpone or prevent dominant type-2 diabetes mellitus breaking-out.
In addition, the pharmaceutical composition and pharmaceutical dosage form of the present invention have the patient of insulin-dependent particularly suitable for treatment, Controlled through insulin or insulin derivates or insulin substitution object or the preparation comprising insulin or derivatives thereof or substitute The patient for treating or will treat or need through it to treat.These patients include type 2 diabetes patient and type-1 diabetes mellitus patient.
Therefore, a preferred embodiment according to the present invention, provide in patient in need improve glycemic control and/ Or the method for reducing fasting plasma glucose, Post-prandial plasma glucose and/or glycosylated hemoglobin HbA1c, the patient is after diagnosing (IGT), impaired fasting glucose (IFG), insulin resistance, metabolic syndrome and/or II types or I types are reduced with glucose tolerance Diabetes, it is characterised in that the pharmaceutical composition or pharmaceutical dosage form of contextual definition are given to patient.
In accordance with another preferred embodiment of the present invention, the improvement II type sugar of the supplementary means as diet and movement is provided The method of urine patient, the especially glycemic control of adult patient.
It can find, by using the pharmaceutical composition or pharmaceutical dosage form of the present invention, even if the trouble insufficient in glycemic control Person through antidiabetic medicine treatment, such as melbine through maximum recommended or tolerance dose, SGLT2 (although although especially press down Preparation or the treatment of DPPIV inhibitor oral monotherapies but the still insufficient patient of glycemic control) in can also realize glycemic control Improvement.The maximum recommended dosage of melbine 850mg or its any equivalent for for example daily 2000mg or three times a day.This The maximum recommended dosage of invention SGLT2 inhibitor, especially compound (I.3) is for such as once a day 100mg, preferably 50mg or very To 25mg or its any equivalent.The maximum recommended dosage of BI 1356 is such as once a day 10mg, preferably 5mg or its is any Equivalent.
Therefore, method of the invention and/or purposes are advantageously used in the trouble of display one kind, two or more following illnesss Person：
(a) using independent diet and movement and glycemic control is insufficient；
Although (b) having carried out the oral monotherapy of melbine, although especially having carried out maximum recommended or tolerance dose Melbine oral monotherapy, but glycemic control is still insufficient；
Although (c) having carried out the oral monotherapy of another antidiabetic, although especially carried out maximum recommended or The oral monotherapy of other antidiabetics of tolerance dose, but glycemic control is still insufficient；
Although (d) having carried out the oral monotherapy of SGLT2 inhibitor, although especially having carried out maximum recommended or tolerance agent The oral monotherapy of the SGLT2 inhibitor of amount, but glycemic control is still insufficient；
Although (e) having carried out the oral monotherapy of DPPIV inhibitor, although especially having carried out maximum recommended or tolerance agent The oral monotherapy of the DPPIV inhibitor of amount, but glycemic control is still insufficient.
Blood-sugar content caused by benzene derivative by the glucopyranosyl substitution for giving the present invention reduces and insulin It is unrelated.Therefore, pharmaceutical composition of the invention suffers from the patient of one or more following illnesss particularly suitable for treatment after diagnosing：
Insulin resistance,
Hyperinsulinemia,
Pre-diabetes,
Type-2 diabetes mellitus, especially late Type II diabetes,
Type-1 diabetes mellitus.
In addition, the pharmaceutical composition and pharmaceutical dosage form of the present invention suffer from below one or more after diagnosing particularly suitable for treatment The patient of illness：
(a) obesity (including I grades, II grades and/or III level obesity), visceral obesity and/or abdominal obesity,
(b) triglycerides blood content >=150mg/dL,
(c) female patient HDL- cholesterol blood levels<40mg/dL and male patient<50mg/dL,
(d) systolic pressure >=130mm Hg and diastolic pressure >=85mm Hg,
(e) fasting blood-glucose content >=100mg/dL.
Think that suffering from glucose tolerance after diagnosing reduces (IGT), impaired fasting glucose (IFG), insulin resistance and/or generation Thank to patient evolution's angiocardiopathy (such as myocardial infarction, coronary heart disease, cardiac dysfunction, thromboembolic events) of syndrome Risk increases.The glycemic control of the present invention may make cardiovascular risk to reduce.
The pharmaceutical composition and pharmaceutical dosage form of the present invention shows good security situation.Therefore, treatment of the invention or Prevent to avoiding using the monotherapy of another antidiabetic (such as melbine) and/or to these drugs of therapeutic dose The patient not tolerated may be advantageous.The treatment or prevention of the present invention are especially to showing one or more following illnesss or having risk The patient of increased one or more following illnesss may be advantageous：Renal insufficiency or nephrosis, heart disease, heart failure, hepatopathy, Tuberculosis, the catabolism state of lactic acidosis (catabolytic state) and/or dangerous or period of pregnancy or nursing period Female patient.
It moreover has been found that giving pharmaceutical composition of the invention or pharmaceutical dosage form without hypoglycemia risk or hypoglycemia risk It is low.Therefore, treatment or prevention of the invention there may also be display hypoglycemia or the increased patient of risk for suffering from hypoglycemia Profit.
The pharmaceutical composition or pharmaceutical dosage form of the present invention is particularly suited in type 2 diabetes patient's Long-term therapy or prevention Disease described in context and/or illness control particularly suitable for its long-term blood glucose.
Term as used in context is " long-term " to indicate that the treatment to patient or the time being administered to patient are longer than 12 weeks, excellent Choosing is longer than 25 weeks, is even more preferably longer than 1 year.
Therefore, of the invention one particularly preferred embodiment, which provides, improves and (especially improves for a long time) diabetes patient Person, especially late Type II diabetes patient especially also suffer from overweight, obesity (including I grades, II grades and/or III level after diagnosing Obesity), the therapy (preferably oral therapies) of the glycemic control of the patient of visceral obesity and/or abdominal obesity.
Method described in all contexts and on the way, especially in treatment, the methods of preventing, preferably once a day to Patient gives the pharmaceutical composition or pharmaceutical dosage form of the present invention.
It can be tested by animal model as known in the art and in clinical studies any of above in the scope of the invention Composition and dosage form.In the following, it is described that the pharmacologic correlation matter of the pharmaceutical composition and dosage form of the invention suitable for assessment Experiment in vivo：
In such as db/db mouse, ob/ob mouse, Zucker Fatty (fa/fa) rats or Zucker Diabetic Tested during the hereditary hyperinsulinism of Fatty (ZDF) rat is courageous and upright or diabetic keratopathy animal the pharmaceutical composition of the present invention, dosage form and Method.In addition, it can be such as through the pretreated HanWistar or Sprague Dawley of streptozocin (streptozotocin) It is tested in the animal of the experiment induced Diabetic of rat.
The pharmaceutical composition of the present invention can be tested in oral glucose tolerance test in animal model described above And influence of the dosage form to glycemic control.After carrying out oral glucose stimulation (challenge) in the animal at one night of fasting, chase after Track blood glucose changes with time.It is reduced by measured peak concentration of glucose or glucose AUC reduces, show the present composition And dosage form significantly improves glucose oscillation (glucose excursion) than each monotherapy.In addition, in animal described above It, can be by measuring the HbA1c in blood after repeatedly giving independent active pharmaceutical ingredients and pharmaceutical composition or dosage form in model Value determines the effect to glycemic control.Compared with each monotherapy, the present composition and dosage form significantly reduce HbA1c.
In animal model described above, in oral glucose tolerance test after single-dose, controlling for the present invention is shown Treat the dependence that can improve to insulin.After carrying out glucose stimulation in fasting one night animal, tracking plasma insulin is at any time Between variation.Compared with independent BI 1356, the present composition and dosage form will show relatively low pancreas islet under relatively low blood glucose fluctuation Plain Cmax or INSULIN A UC.
Can by an empty stomach or Postprandial under measure the blood plasma of animal model described above in active GLP-1 contents, To determine the increase of these contents caused by treatment of the invention after single or multiple administrations.Equally, it can survey under the same conditions Measure the reduction of glucagons content in blood plasma.Compared with the benzene derivative that glucopyranosyl substitution is used alone, of the present invention group Greater activity GLP-1 concentration and relatively low glucagon concentration will be shown by closing object and dosage form.
Insulin content can be measured after multiple dosing in animal model described above to increase or in pancreas slice by exempting from It is measured in the increased β cell qualities of institute or the separated pancreas islet of measurement by morphometric Analysis method after epidemic disease histochemical stain The insulin secretion increase that glucose is stimulated determine the present composition and dosage form to β cytothesises and new life it is excellent Effect.
Pharmacological examples
Beneficial effect of the following embodiment display present invention combination to glycemic control.
Embodiment I：
According to first embodiment, in 9 week old male Zucker Diabetic Fatty (ZDF) rats of overnight fasting (ZDF/Crl-Leprfa) in carry out oral glucose tolerance test.Blood sample before taking blood to obtain administration by tail portion.Use blood glucose Instrument measures blood glucose, and animal is grouped at random and is used for blood sugar test (every group of n=5).Then, each group receives single oral administration Independent medium (0.5% hydroxyethyl cellulose aqueous solution containing 3mM HCl and 0.015%Polysorbat80) contains SGLT2 Inhibitor or DPPIV inhibitor or SGLT2 inhibitor add the medium of the combination of DPP IV inhibitor.After giving compound 30 minutes, animal received oral glucose load (2g/kg).30 minutes, 60 minutes, 90 minutes, 120 minutes after glucose stimulation And 180 minutes, measure the blood glucose in tail blood.It is fluctuated come quantifying glucose by calculating reactivity glucose AUC.Data with Average value ± SEM is indicated.Come statistical comparison control group and work using two-way unpaired Students t test (Student's t test) Property group.
As a result it is shown in Fig. 3." compound A " is the BI 1356 of 1mg/kg dosage.Compound B is 3mg/kg dosage Compound (I.3), the i.e. chloro- 4- of 1- (β-D- glucopyranose -1- bases) -2- [4- ((S)-tetrahydrofuran -3- bases oxygroup)-benzyls Base]-benzene.Combine the combination of BI 1356 and compound (I.3) that A+B is same dose.P values relative to control group are by column Scheme the symbolic indication of top.It combines and is shown in (*, p below figure relative to the P values of monotherapy<0.05；*, p<0.01；* *, p <0.001).BI 1356 makes glucose oscillation reduce 56%, (I.3) compound makes glucose oscillation reduce 51%.Oral In dextrose tolerance test, combination makes glucose oscillation reduce 84%, and glucose AUC reduces relative to each monotherapy It is though statistically significant.
Embodiment II：
According to second embodiment, in the overnight fasting male Sprague Dawley rats (Crl that weight is about 200g: CD (SD)) in carry out oral glucose tolerance test.Blood sample before taking blood to obtain administration by tail portion.Blood is measured with blood glucose meter Sugar, and animal is grouped at random and is used for blood sugar test (every group of n=5).Then, each group receives the independent medium that single oral is given (0.5% hydroxyethyl cellulose aqueous solution containing 0.015%Polysorbat80) or inhibit containing SGLT2 inhibitor or DPPIV Agent or the third antidiabetic or SGLT2 inhibitor add DPP IV inhibitor add the third antidiabetic combination matchmaker It is situated between.Alternatively, each group receives the independent medium that single oral is given or adds the third containing SGLT2 inhibitor or DPPIV inhibitor Antidiabetic or the third antidiabetic or SGLT2 inhibitor add DPP IV inhibitor to add the third antidiabetic The medium of combination.30 minutes after to drug compound, animal receives oral glucose load (2g/kg).Glucose stimulates it 30 minutes afterwards, 60 minutes, 90 minutes and 120 minutes measure the blood glucose in tail blood.By calculating reactive glucose AUC Carry out quantifying glucose fluctuation.Data are indicated with average value ± S.E.M.Statistical comparison is carried out by student's t methods of inspection.
Embodiment III：Treat pre-diabetes
The pharmaceutical composition or pharmaceutical dosage form that the clinical research test present invention can be used are being treated with pathologic empty stomach grape Sugar and/or glucose tolerance reduce effect in the pre-diabetes being characterized.Research in short period of time (such as 2-4 weeks) In, by measuring fasting glucose value and/or postprandial or Road test after the treatment period of research (set into postprandial Oral glucose tolerance test or food tolerance test) after dextrose equivalent, and by its with research start before these These of value and/or placebo value relatively examine treatment successful.In addition, fructosamine can be measured before treatment and later (fructosamine) value, and compared with initial value and/or placebo value.The significant decrease of empty stomach or non-empty stomach glucose content Confirm therapeutic efficiency.In the research of longer term (12 weeks or 12 weeks or more), by measure HbA1c values, with initial value and/or Placebo class value relatively tests treatment successful.Compared with initial value and/or placebo value, HbA1c values significantly change card Composition of the invention or dosage form is illustrated for the effect for the treatment of pre-diabetes.
Embodiment IV：Prevent dominant type-2 diabetes mellitus
Treatment pathologic fasting glucose and/or glucose tolerance reduce (pre-diabetes) patient and also pursue prevention transformation At the target of dominant type-2 diabetes mellitus.Therapeutic efficiency can be investigated in comparative clinical research, wherein with the medicine group of the present invention Close the treatment pre-diabetes patient of object or placebo or non-drug therapy or other medicines through overlength period (such as 1-5). During treatment and when treatment end, tested by measuring fasting glucose and/or Road test (such as oGTT), with true Fixed how many patients show dominant type-2 diabetes mellitus, such as fasting glucose content>125mg/dl and/or according to 2 hours of oGTT Value>199mg/dl.Compared with a kind for the treatment of of other forms, when being treated with the pharmaceutical composition of the present invention or dosage form, display is aobvious Property type 2 diabetes patient's quantity substantially reduce, it was demonstrated that the effect of preventing from pre-diabetes to be transformed into overt diabetes.
Embodiment V：Treat type-2 diabetes mellitus
Type 2 diabetes patient is treated with the pharmaceutical composition of the present invention or dosage form, in addition to being generated to glucose metabolism situation Outside quickly improving, the also long-term metabolism status that prevents deteriorates.The longer term can be being treated with the pharmaceutical composition of the present invention or dosage form (such as 3 months to 1 year or even 1 to 6 year) and compared with the patient of placebo or the treatment of other antidiabetic medicines This result is observed in patient.If observing, fasting glucose and/or HbA1c values do not increase or are only increased slightly, evidence table It is bright with placebo or other antidiabetic medicines treatment patient compared with, treat successfully.If with the trouble treated with other medicines Person compares, and the glucose metabolism situation with the pharmaceutical composition of the present invention or the patient of dosage form treatment of notable small percentage is disliked Change (such as HbA1c values increase to>6.5% or>7%) it is needed to instruction with additional oral antidiabetic drug or insulin or pancreas islet The degree of plain analogue treatment then further obtains evidence and shows to treat successfully.
Embodiment VI：Treat insulin resistance
In the clinical research of different time length (such as 2 weeks to 12 months), the normal blood of hyperinsulinemia-is used Sugared clamp is studied to examine treatment successful.Compared with initial value or placebo or giving the group of different therapy, tied in research Glucose infusion rate significantly increases when beam, it was demonstrated that the work(of pharmaceutical composition or dosage form the treatment insulin resistance of the present invention Effect.
Embodiment VII：Treat hyperglycemia
In the clinical research of different time length (such as 1 day to 24 months), by measuring fasting glucose or non-empty Abdomen glucose (such as after postprandial or oGTT Road tests or limiting into postprandial) examines the treatment success in hyperglycemic subject Property.Compared with initial value or placebo or giving the group of different therapy, these glucose during research or at the end of research Value significantly reduces, it was demonstrated that the effect of pharmaceutical composition or dosage form the treatment hyperglycemia of the present invention.
Embodiment VIII：Prevent capilary or macrovascular complications
With the pharmaceutical composition of the present invention or dosage form treatment type-2 diabetes mellitus or pre-diabetes patient, prevents or reduce Microvascular complication (such as diabetic neuropathy, diabetic retinopathy, nephrosis, diabetes, sugar Urinate characteristic of disease ulcer) or macrovascular complications (such as myocardial infarction, acute coronary syndrome, unstable angina pectoris, stabilization Type angina pectoris, apoplexy, peripheral occlusive arterial disease, cardiomyopathy, heart failure, arrhythmia cordis, reangiostenosis) or reduce Develop the risk of these complication.It is long-term with the combination of the active ingredient of the pharmaceutical composition of the present invention or dosage form or the present invention (such as 1-6) treats type-2 diabetes mellitus or pre-diabetes patient, and with other antidiabetic medicines or placebo The patient for the treatment of compares.It is solitary or multiple concurrent compared with the patient of other antidiabetic medicines or placebo treatment The negligible amounts of disease show to treat successfully.In the situation of big vascular events, diabetes and/or diabetic ulcer, pass through Medical history and various test number of computations.In the situation of diabetic retinopathy, by carrying out electricity to eyeground The illumination of brain control and assessment or other ophtamological methods determine treatment successful.In the situation of diabetic neuropathy, Other than medical history and clinical examination, the tuning fork of such as calibration also can be used to measure nerve conduction velocity.About diabetes Property nephrosis, can before the study starts, research during and research at the end of study following parameter：Albumin secretion, kreatinin are clear Except rate, serum creatinine value, serum creatinine value double the time used, until must dialyse the time used.
Embodiment IX：Treat metabolic syndrome
It can be in the clinical research of different time length (such as 12 weeks to 6 years) by measuring fasting glucose or non-empty stomach Glucose (such as after postprandial or oGTT Road tests or limiting into postprandial) or HbA1c values test the pharmaceutical composition of the present invention Or the effect of dosage form.Compared with initial value or placebo or giving the group of different therapy, during research or at the end of research These dextrose equivalents or HbA1c values significantly reduce, it was demonstrated that the pharmaceutical composition of the present invention or dosage form treatment metabolic syndrome Effect.The example is the systolic pressure compared with the initial value studied when starting or the patient group treated with placebo or different therapy And/or diastolic pressure reduction, plasma triglyceride reduction, total cholesterol or LDL cholesterol reduction, the raising of HDL cholesterol or weight It reduces.
The embodiment of pharmaceutical composition and pharmaceutical dosage form
Hereinafter, term " API 1 " indicates the benzene derivative of formula (I) glucopyranosyl substitution, especially compound (I.3), preferably its crystal form (I.3X), and term " API 2 " expression BI 1356.
Active medicine is ground with such as needle mill (pin-mill) or the suitable grinder of jet mill (jet-mill) Composition, i.e. BI 1356 and compound (I.3), preferably crystal form (I.3X), to be obtained before preparing pharmaceutical composition or dosage form Obtain required size distribution.
The example of typical size Distribution Value X90, X50 and X10 of the preferred active pharmaceutical ingredients of the following table display present invention.
Embodiment 1：Individual layer tablet through once pelletizing
Copolyvidone is dissolved in pure water so that granulation liquid is made under environment temperature (about 20 DEG C).Suitably mixed API 2 and API 1, mannitol, pregelatinized starch and cornstarch are mixed in conjunction machine so that premix is made.Use granulation liquid Soak premix, and then granulation.Particle through the screening wetting of suitable sieve.It is being fluidized in about 60 DEG C of entering air temperatures Dry particle in bed dryer is until loss on drying value is 1-4%.Through that the sieve screening that screen size is 1.0 mm is dry Grain.
Magnesium stearate with deblocking and is added in particle across sieve.Then, by final in suitable mixing machine 3 minutes obtained final mixtures are mixed, and 8 mm disk cores are pressed into the press power of 15 kN.
In environment temperature by hydroxypropyl methyl cellulose, polyethylene glycol, talcum powder, titanium dioxide in suitable mixing machine And iron oxide is suspended in pure water so that film coating suspension (coating suspension) is made.With film coating suspension covering piece Core is until weight increase is about 3%, thin membrane coated tablet is made.It can get following preparation：
Ingredient Mg/ pieces Mg/ pieces Mg/ pieces Mg/ pieces Mg/ pieces
API1 2.5 5.0 10.0 25.0 50.0
API2 5.0 5.0 5.0 5.0 5.0
Mannitol 128.4 125.9 120.9 105.9 80.9
Pregelatinized starch 18.0 18.0 18.0 18.0 18.0
Cornstarch 18.0 18.0 18.0 18.0 18.0
Copolyvidone 5.4 5.4 5.4 5.4 5.4
Magnesium stearate 2.7 2.7 2.7 2.7 2.7
Film coating 5.0 5.0 5.0 5.0 5.0
It amounts to 185.0 185.0 185.0 185.0 185.0
The tablet hardness of gained tablet is about 85N, and friability is less than 0.5%.Content uniformity meets the requirement of USP.Disintegration When be limited to about 7 minutes, and API1 and the dissolution rates of API2 over the course of 15 mins are all higher than 85%, such as API1 is 97% and API2 is 101%。
Embodiment 2：Individual layer tablet through once pelletizing
Copolyvidone is dissolved in pure water so that granulation liquid is made in environment temperature.It is mixed in suitable mixing machine API1, API2, mannitol, pregelatinized starch and cornstarch are to be made premix.Premix is soaked with granulation liquid, And then granulation.Particle through the screening wetting of suitable sieve.It is done in fluidized bed dryer in about 60 DEG C of entering air temperatures Dry particle is until loss on drying value is 1-4%.Through the particle that the sieve screening that screen size is 1.0mm is dry.
Magnesium stearate with deblocking and is added in particle across sieve.Then, by final in suitable mixing machine 3 minutes obtained final mixtures are mixed, and 8mm disk cores are pressed into the press power of 17kN.
In environment temperature by hydroxypropyl methyl cellulose, polyethylene glycol, talcum powder, titanium dioxide in suitable mixing machine And iron oxide is suspended in pure water so that film coating suspension is made.With film coating suspension cladding label until weight increase is about 3%, thin membrane coated tablet is made.It can get following preparation：
Ingredient Mg/ pieces Mg/ pieces Mg/ pieces Mg/ pieces Mg/ pieces
API1 2.5 5.0 10.0 25.0 50.0
API2 5.0 5.0 5.0 5.0 5.0
Mannitol 127.5 125.0 120.0 105.0 80.0
Pregelatinized starch 18.0 18.0 18.0 18.0 18.0
Cornstarch 18.0 18.0 18.0 18.0 18.0
Copolyvidone 5.4 5.4 5.4 5.4 5.4
Magnesium stearate 3.6 3.6 3.6 3.6 3.6
Film coating 5.0 5.0 5.0 5.0 5.0
It amounts to 185.0 185.0 185.0 185.0 185.0
Tablet hardness, friability, content uniformity, disintegration time limited and Dissolution behaviours are measured as described above.
Embodiment 3：Individual layer tablet through once pelletizing
Copolyvidone is dissolved in pure water so that granulation liquid is made in environment temperature.It is mixed in suitable mixing machine API1, API2, mannitol, pregelatinized starch and cornstarch are to be made premix.Premix is soaked with granulation liquid, And then granulation.Particle through the screening wetting of suitable sieve.It is done in fluidized bed dryer in about 60 DEG C of entering air temperatures Dry particle is until loss on drying value is 1-4%.Through the particle that the sieve screening that screen size is 1.0mm is dry.To dry particle Middle addition Crospovidone and mixing 5 minutes be made Master Mix.Magnesium stearate with deblocking and is added to master across sieve It wants in mixture.Then, by finally mixing 3 minutes obtained final mixtures in suitable mixing machine, and with the pressure of 16kN System, which forces, is made 8mm disk cores.
In environment temperature by hydroxypropyl methyl cellulose, polyethylene glycol, talcum powder, titanium dioxide in suitable mixing machine And iron oxide is suspended in pure water so that film coating suspension is made.With film coating suspension cladding label until weight increase is about 3%, thin membrane coated tablet is made.It can get following preparation：
Ingredient Mg/ pieces Mg/ pieces Mg/ pieces Mg/ pieces Mg/ pieces
API1 2.5 5.0 10.0 25.0 50.0
API2 5.0 5.0 5.0 5.0 5.0
Mannitol 127.5 125.0 120.0 105.0 80.0
Pregelatinized starch 18.0 18.0 18.0 18.0 18.0
Cornstarch 18.0 18.0 18.0 18.0 18.0
Crospovidone 2.0 2.0 2.0 2.0 2.0
Copolyvidone 5.4 5.4 5.4 5.4 5.4
Magnesium stearate 3.6 3.6 3.6 3.6 3.6
Film coating 5.0 5.0 5.0 5.0 5.0
It amounts to 187.0 187.0 187.0 187.0 187.0
Tablet hardness, friability, content uniformity, disintegration time limited and Dissolution behaviours are measured as described above.
Embodiment 4：Individual layer tablet through pelletizing twice
Carry out each granulation respectively for only containing a kind of active pharmaceutical ingredients twice.When this pelletizes twice, in environment temperature Copolyvidone is dissolved in pure water so that granulation liquid is made.
API2, mannitol, pregelatinized starch and cornstarch are mixed in suitable mixing machine so that premix is made. Premix, and then granulation are soaked with granulation liquid.Particle through the screening wetting of suitable sieve.In about 60 DEG C of intake airs Temperature in fluidized bed dryer dry particle until loss on drying value be 1-4%.It is sieved through the sieve that screen size is 1.0mm Dry particle.
API1, mannitol, pregelatinized starch, cornstarch and optional pigment are mixed in suitable mixing machine (such as Iron oxide red) premix is made.Premix, and then granulation are soaked with granulation liquid.It sieves and moistens through suitable sieve Wet particle.About 60 DEG C of entering air temperatures in fluidized bed dryer dry particle until loss on drying value be 1-4%.Through The particle for the sieve screening drying that screen size is 1.0mm.
Merge two kinds of particles, add Crospovidone and mix all components in suitable mixing machine 5 minutes, master is made Want mixture.Magnesium stearate with deblocking and is added in Master Mix across sieve.Then, by suitable mixing machine In finally mix 3 minutes obtained final mixtures, and 15 × 6mm ellipse labels are pressed into the press power of 17kN.It can get Following preparation：
Ingredient Mg/ pieces Mg/ pieces Mg/ pieces Mg/ pieces Mg/ pieces
It pelletizes for the first time
API1 2.5 5.0 10.0 25.0 50.0
Mannitol 123.5 121.0 116.0 101.0 76.0
Pregelatinized starch 18.0 18.0 18.0 18.0 18.0
Cornstarch 18.0 18.0 18.0 18.0 18.0
Iron oxide red 2.7 2.7 2.7 2.7 2.7
Copolyvidone 5.4 5.4 5.4 5.4 5.4
Second of granulation
API2 5.0 5.0 5.0 5.0 5.0
Mannitol 130.9 130.9 130.9 130.9 130.9
Pregelatinized starch 18.0 18.0 18.0 18.0 18.0
Cornstarch 18.0 18.0 18.0 18.0 18.0
Copolyvidone 5.4 5.4 5.4 5.4 5.4
Final mixing
Magnesium stearate 7.2 7.2 7.2 7.2 7.2
Crospovidone 5.4 5.4 5.4 5.4 5.4
It amounts to 360.0 360.0 360.0 360.0 360.0
The tablet hardness of gained tablet is about 105N.Content uniformity meets the requirement of USP.Friability is less than 0.5%.It collapses It is limited to when solution about 5 minutes, and the dissolution rates of two kinds of API over the course of 15 mins are all higher than 85%.
Embodiment 5：Individual layer tablet through pelletizing twice
Carry out each granulation respectively for only containing a kind of active pharmaceutical ingredients twice.
Copolyvidone is dissolved in pure water so that granulation liquid is made in environment temperature.It is mixed in suitable mixing machine API2, mannitol, pregelatinized starch and cornstarch are to be made premix.With granulation liquid soak premix, and with After pelletize.Particle through the screening wetting of suitable sieve.In the drying in fluidized bed dryer of about 60 DEG C of entering air temperatures Grain is until loss on drying value is 1-4%.Through the particle that the sieve screening that screen size is 1.0mm is dry.
API1, mannitol, microcrystalline cellulose, hydroxypropyl cellulose and optional pigment are mixed in suitable mixing machine (such as iron oxide red) is to be made premix.Premix, and then granulation are soaked with pure water.It sieves and moistens through suitable sieve Wet particle.About 60 DEG C of entering air temperatures in fluidized bed dryer dry particle until loss on drying value be 1-4%.Through The particle for the sieve screening drying that screen size is 1.0mm.
Merge two kinds of particles, add Crospovidone and mix all components in suitable mixing machine 5 minutes, master is made Want mixture.Magnesium stearate with deblocking and is added in Master Mix across sieve.Then, by suitable mixing machine In finally mix 3 minutes obtained final mixtures, and 15 × 6mm ellipse labels are pressed into the press power of 15kN.It can get Following preparation：
Ingredient Mg/ pieces Mg/ pieces Mg/ pieces Mg/ pieces Mg/ pieces
It pelletizes for the first time
API1 2.5 5.0 10.0 25.0 50.0
Mannitol 123.5 121.0 116.0 101.0 76.0
Microcrystalline cellulose 36.0 36.0 36.0 36.0 36.0
Iron oxide red 2.7 2.7 2.7 2.7 2.7
Hydroxypropyl cellulose 5.4 5.4 5.4 5.4 5.4
Second of granulation
API2 5.0 5.0 5.0 5.0 5.0
Mannitol 130.9 130.9 130.9 130.9 130.9
Pregelatinized starch 18.0 18.0 18.0 18.0 18.0
Cornstarch 18.0 18.0 18.0 18.0 18.0
Copolyvidone 5.4 5.4 5.4 5.4 5.4
Final mixing
Magnesium stearate 7.2 7.2 7.2 7.2 7.2
Crospovidone 5.4 5.4 5.4 5.4 5.4
It amounts to 360.0 360.0 360.0 360.0 360.0
Tablet hardness, friability, content uniformity, disintegration time limited and Dissolution behaviours are measured as described above.
Embodiment 6：Bilayer tablet through pelletizing twice
Carry out each granulation respectively for only containing a kind of active pharmaceutical ingredients twice.When this pelletizes twice, in environment temperature Copolyvidone is dissolved in pure water so that granulation liquid is made.
API2, mannitol, pregelatinized starch and cornstarch are mixed in suitable mixing machine so that premix is made. Premix, and then granulation are soaked with granulation liquid.Particle through the screening wetting of suitable sieve.In about 60 DEG C of intake airs Temperature in fluidized bed dryer dry particle until loss on drying value be 1-4%.It is sieved through the sieve that screen size is 1.0mm Dry particle.
API1, mannitol, pregelatinized starch, cornstarch and optional pigment are mixed in suitable mixing machine (such as Iron oxide red) premix is made.Premix, and then granulation are soaked with granulation liquid.It sieves and moistens through suitable sieve Wet particle.About 60 DEG C of entering air temperatures in fluidized bed dryer dry particle until loss on drying value be 1-4%.Through The particle for the sieve screening drying that screen size is 1.0mm adds Crospovidone and mixes each component 5 in suitable mixing machine Minute.
Magnesium stearate with deblocking and is added separately in pelletizing twice across sieve.Then, by suitably mixing It is finally mixed in machine 3 minutes and two kinds of final mixtures is made.The first layer of bilayer tablet uses the final mixture containing API1, And the second layer uses the final mixture containing API2.Bilayer tablet is prepared on suitable tablet press machine, wherein being used for first layer The first press power be 2kN, and prepares the main press powers of 10mm circular dies as 12kN.It can get following preparation：
Ingredient Mg/ pieces Mg/ pieces Mg/ pieces Mg/ pieces Mg/ pieces
First layer
API1 2.5 5.0 10.0 25.0 50.0
Mannitol 123.5 121.0 116.0 101.0 76.0
Pregelatinized starch 18.0 18.0 18.0 18.0 18.0
Cornstarch 18.0 18.0 18.0 18.0 18.0
Iron oxide red 2.7 2.7 2.7 2.7 2.7
Copolyvidone 5.4 5.4 5.4 5.4 5.4
Magnesium stearate 4.5 4.5 4.5 4.5 4.5
Crospovidone 5.4 5.4 5.4 5.4 5.4
The second layer
API2 5.0 5.0 5.0 5.0 5.0
Mannitol 130.9 130.9 130.9 130.9 130.9
Pregelatinized starch 18.0 18.0 18.0 18.0 18.0
Cornstarch 18.0 18.0 18.0 18.0 18.0
Copolyvidone 5.4 5.4 5.4 5.4 5.4
Magnesium stearate 2.7 2.7 2.7 2.7 2.7
It amounts to 360.0 360.0 360.0 360.0 360.0
The tablet hardness of gained tablet is about 120N, and friability is less than 0.5%.Content uniformity meets the requirement of USP.It collapses It is limited to when solution about 6 minutes, and the dissolution rates of two kinds of API over the course of 15 mins are all higher than 85%.
Embodiment 7：Bilayer tablet through pelletizing twice
Carry out each granulation respectively for only containing a kind of active pharmaceutical ingredients twice.
Copolyvidone is dissolved in pure water so that granulation liquid is made in environment temperature.It is mixed in suitable mixing machine API2, mannitol, pregelatinized starch and cornstarch are to be made premix.With granulation liquid soak premix, and with After pelletize.Particle through the screening wetting of suitable sieve.In the drying in fluidized bed dryer of about 60 DEG C of entering air temperatures Grain is until loss on drying value is 1-4%.Through the particle that the sieve screening that screen size is 1.0mm is dry.
API1, mannitol, microcrystalline cellulose, hydroxypropyl cellulose and optional pigment are mixed in suitable mixing machine (such as iron oxide red) is to be made premix.Premix, and then granulation are soaked with pure water.It sieves and moistens through suitable sieve Wet particle.About 60 DEG C of entering air temperatures in fluidized bed dryer dry particle until loss on drying value be 1-4%.Through The particle for the sieve screening drying that screen size is 1.0mm adds Crospovidone and mixes each component 5 in suitable mixing machine Minute.
Magnesium stearate with deblocking and is added separately in pelletizing twice across sieve.Then, by suitably mixing It is finally mixed in machine 3 minutes and two kinds of final mixtures is made.The first layer of bilayer tablet uses the final mixture containing API1, And the second layer uses the final mixture containing API2.Bilayer tablet is prepared on suitable tablet press machine, wherein being used for first layer The first press power be 2kN, and prepares the main press powers of 10mm circular dies as 12kN.It can get following preparation：
Ingredient Mg/ pieces Mg/ pieces Mg/ pieces Mg/ pieces Mg/ pieces
First layer
API1 2.5 5.0 10.0 25.0 50.0
Mannitol 123.5 121.0 116.0 101.0 76.0
Microcrystalline cellulose 36.0 36.0 36.0 36.0 36.0
Iron oxide red 2.7 2.7 2.7 2.7 2.7
Hydroxypropyl cellulose 5.4 5.4 5.4 5.4 5.4
Magnesium stearate 4.5 4.5 4.5 4.5 4.5
Crospovidone 5.4 5.4 5.4 5.4 5.4
The second layer
API2 5.0 5.0 5.0 5.0 5.0
Mannitol 130.9 130.9 130.9 130.9 130.9
Pregelatinized starch 18.0 18.0 18.0 18.0 18.0
Cornstarch 18.0 18.0 18.0 18.0 18.0
Copolyvidone 5.4 5.4 5.4 5.4 5.4
Magnesium stearate 2.7 2.7 2.7 2.7 2.7
It amounts to 360.0 360.0 360.0 360.0 360.0
Tablet hardness, friability, content uniformity, disintegration time limited and Dissolution behaviours are measured as described above.
Embodiment 8：Individual layer tablet through once pelletizing
Copolyvidone is dissolved in pure water so that granulation liquid is made under environment temperature (about 20 DEG C).Suitably mixed API1, API2, mannitol, pregelatinized starch and cornstarch are mixed in conjunction machine so that premix is made.Moistened with granulation liquid Wet premix, and then granulation.Particle through the screening wetting of suitable sieve.In about 60 DEG C of entering air temperatures in fluid bed Dry particle in drier is until loss on drying value is 1-4%.Through the particle that the sieve screening that screen size is 1.0mm is dry.
Crospovidone and talcum powder are added into dry particle and mix 5 minutes so that Master Mix is made.It will be stearic Sour magnesium with deblocking and is added in Master Mix across sieve.Then, by finally being mixed in suitable mixing machine 3 minutes Final mixture is made, and 8mm circular dies are pressed into the press power of 16kN.When API1 and API2 merge in primary granulation And when being then incorporated in a tablet, find the combination of two kinds of lubricant talcum powder and magnesium stearate because assign low knockout press and Final mixture is avoided to be adhered to especially suitable on tablet press.
In environment temperature by hydroxypropyl methyl cellulose, polyethylene glycol, talcum powder, titanium dioxide in suitable mixing machine Titanium, mannitol and iron oxide are suspended in pure water so that film coating suspension is made.With film coating suspension cladding label until weight It is about 3% that amount, which increases, thin membrane coated tablet is made.It can get following preparation：
Ingredient Mg/ pieces Mg/ pieces Mg/ pieces Mg/ pieces Mg/ pieces
API1 2.5 5.0 10.0 25.0 50.0
API2 5.0 5.0 5.0 5.0 5.0
Mannitol 114.0 111.5 106.5 91.5 66.5
Pregelatinized starch 18.0 18.0 18.0 18.0 18.0
Cornstarch 19.8 19.8 19.8 19.8 19.8
Crospovidone 3.6 3.6 3.6 3.6 3.6
Copolyvidone 5.4 5.4 5.4 5.4 5.4
Talcum powder 9.0 9.0 9.0 9.0 9.0
Magnesium stearate 2.7 2.7 2.7 2.7 2.7
Hydroxypropyl methyl cellulose 1.7500 1.7500 1.7500 1.7500 1.7500
Polyethylene glycol 0.6000 0.6000 0.6000 0.6000 0.6000
Iron oxide 0.0125 0.0125 0.0125 0.0125 0.0125
Titanium dioxide 0.7375 0.7375 0.7375 0.7375 0.7375
Talcum powder 0.9000 0.9000 0.9000 0.9000 0.9000
Mannitol 1.0000 1.0000 1.0000 1.0000 1.0000
It amounts to 185.0 185.0 185.0 185.0 185.0
Tablet hardness, friability, content uniformity, disintegration time limited and Dissolution behaviours are measured as described above.
Testing example about pharmaceutical composition and the property of pharmaceutical dosage form
1. disintegration test
According to USP31-NF26S2, disintegration test is carried out described in the 701st chapter (disintegration).
2. dissolution test
Standard dissolution, which is tested, is disclosed in USP31-NF26S2, in the 711st chapter (dissolution rate).The use of mixing speed is 50rpm Paddle method (device 2).The 0.05M kaliumphosphate buffers (pH6.8) that dissolving medium is the 900mL that temperature is 37 DEG C.10,15, 20, it is sampled after 30 and 45 minutes.Sample is analyzed by HPLC.
Fig. 4 describes the dissolution characteristic of the tablet of embodiment 4 and embodiment 6, and wherein API1 is compound (I.3) and API2 is BI 1356.
Fig. 5 describes the dissolution characteristic of the tablet of embodiment 8, and wherein API1 is compound (I.3) and API2 is BI 1356.
3. by laser diffraction measurement size distribution
Such as particle size distribution measurement is carried out by light scattering or laser diffraction technology.In order to measure granularity, for example, by point Powder is fitted into laser diffraction light splitting instrument by throwaway member.Test method is described in detail as follows：
According to the software set instrument for preparing the recommendation of quotient and being provided using quotient is prepared.It is thorough before removing a part of sample Bottom mixes and rolling sample container is to ensure that representative sample is arrived in test.About 100mg samples are transferred to by using spatula It is closed the lid in ASPIROS vials and to bottle to prepare Duplicate samples.The bottle to close the lid is placed in feeder.
4. tablet hardness and friability
Tablet hardness and friability test are carried out according to USP31-NF26S2, described in the 1217th chapter (tablet brisement power).
In conclusion the present invention relates to following technical schemes：
1. pharmaceutical composition, it includes BI 1356s as the first active pharmaceutical ingredients and one or more excipient.
2. the pharmaceutical composition of technical solution 1 also includes the benzene derivative of formula (I) glucopyranosyl substitution
Wherein R1Indicate chlorine or methyl；And R3Indicate ethyl, acetenyl, ethyoxyl, (R)-tetrahydrofuran -3- bases oxygroup or (S)-tetrahydrofuran -3- bases oxygroup or its prodrug, as the second active pharmaceutical ingredients.
3. the pharmaceutical composition of technical solution 1, the wherein size distribution of first active ingredient are X90<200μm.
4. the pharmaceutical composition of technical solution 2 or 3, the wherein size distribution of second active ingredient are 1 μm<X90<200μ m。
5. the pharmaceutical composition of any one of technical solution 1,2,3 or 4, wherein one or more excipient include one kind Or plurality of diluent.
6. the pharmaceutical composition of any one of technical solution 1,2,3 or 4, wherein one or more excipient include one kind Or plurality of diluent and one or more adhesives.
7. the pharmaceutical composition of any one of technical solution 1,2,3 or 4, wherein one or more excipient include one kind Or plurality of diluent, one or more adhesives and one or more disintegrants.
8. the pharmaceutical composition of any one of above-mentioned technical proposal, it includes
0.5-25% one or two active ingredients,
The one or more diluents of 40-88%,
The one or more adhesives of 0.5-20%, and
The one or more disintegrants of 0.5-20%,
Wherein percentage is the weight percent of total composition.
9. the pharmaceutical composition of any one of technical solution 1-8, in granule, capsule, tablet or thin membrane coated tablet Form.
10. pharmaceutical dosage form, it includes the pharmaceutical compositions of any one of technical solution 1 to 9.
11. the pharmaceutical dosage form of technical solution 10, it is characterised in that it is solid pharmaceutical dosage formulation, in particular capsule or tablet.
12. the pharmaceutical dosage form of technical solution 10 or 11, it includes the BI 1356s of 0.1 to 30mg amount as the first activity Pharmaceutical compositions.
13. the pharmaceutical dosage form of any one of technical solution 10,11 or 12 also includes the technical side of 0.5 to 100mg amount The benzene derivative of formula (I) glucopyranosyl substitution defined in case 2 is as the second active pharmaceutical ingredients.
14. the pharmaceutical dosage form of any one of technical solution 10,11,12 or 13, it is characterised in that in dissolution is tested, 45 After minute, at least first active pharmaceutical ingredients of first active pharmaceutical ingredients of 75 weight % or at least 75 weight % and at least Second active pharmaceutical ingredients of 75 weight % dissolve.
15. the pharmaceutical dosage form of any one of technical solution 10,11,12,13 or 14, it is characterised in that in disintegration test, The pharmaceutical dosage form is disintegrated in 30 minutes.
16. a kind of method of the pharmaceutical dosage form of any one of technology of preparing scheme 10-15 comprising one or more granulation Step, wherein the one or two active pharmaceutical ingredients are pelletized together with one or more excipient.
17. preventing dysbolism, the progress for slowing down the dysbolism, delay in the patient of needs or treating metabolism barrier The method hindered, the dysbolism are selected from：Type-1 diabetes mellitus, type-2 diabetes mellitus, glucose tolerance reduction, impaired fasting glucose, high blood Sugared disease, post prandial hyperglycemia, overweight, obesity and metabolic syndrome, it is characterised in that appoint into patient's medicine-feeding technology scheme 1-9 One pharmaceutical composition or the pharmaceutical dosage form of any one of technical solution 10-15.
18. improving glycemic control in patient in need and/or reducing fasting plasma glucose, Post-prandial plasma glucose And/or the method for glycosylated hemoglobin HbA1c, it is characterised in that the drug of any one of patient's medicine-feeding technology scheme 1-9 The pharmaceutical dosage form of any one of composition or technical solution 10-15.
19. preventing in patient in need, slowing down, postponing or the reduction of reverses glucose tolerance, impaired fasting glucose, pancreas Island element resistance and/or metabolic syndrome are into the method for transforming into type-2 diabetes mellitus, it is characterised in that patient's medicine-feeding technology scheme 1-9 Any one of pharmaceutical composition or any one of technical solution 10-15 pharmaceutical dosage form.
20. preventing illness selected from the following or obstacle in patient in need, the progress that slows down the illness or obstacle, prolonging Late or treat the illness or the method for obstacle：Diabetic complication, such as cataract and capilary and macrovascular diseases, such as kidney Disease, retinopathy, neuropathy, tissue ischemia, diabetes, artery sclerosis, myocardial infarction, acute coronary syndromes Sign, unstable angina pectoris, stable angina cordis, apoplexy, peripheral occlusive arterial disease, cardiomyopathy, heart failure, the rhythm of the heart lose Normal and reangiostenosis, it is characterised in that the pharmaceutical composition or technical solution of any one of patient's medicine-feeding technology scheme 1-9 The pharmaceutical dosage form of any one of 10-15.
21. weight gain is lost weight or prevented in patient in need or promotes the method lost weight, feature It is the drug agent of the pharmaceutical composition or any one of technical solution 10-15 to any one of patient's medicine-feeding technology scheme 1-9 Type.
22. the pharmaceutical composition of any one of technical solution 1-9 is being prepared in patient in need for realizing following Purposes in the drug of purpose：
The dysbolism is treated in prevention dysbolism selected from the following, the progress for slowing down the dysbolism, delay：I types It is diabetes, type-2 diabetes mellitus, glucose tolerance reduction, impaired fasting glucose, hyperglycemia, post prandial hyperglycemia, overweight, fat Disease and metabolic syndrome；Or
Improve glycemic control and/or reduces fasting plasma glucose, Post-prandial plasma glucose and/or the blood red egg of glycosylation White HbA1c；Or
Prevent, slow down, postponing or reverses glucose tolerance reduces, insulin resistance and/or metabolic syndrome are into transforming into II Patients with type Ⅰ DM；Or
Prevention illness selected from the following or obstacle slow down the illness or obstacle progress, postpone or treat the illness or barrier Hinder：Diabetic complication, such as cataract and capilary and macrovascular diseases, such as nephropathy, retinopathy, neuropathy Change, tissue ischemia, artery sclerosis, myocardial infarction, apoplexy and peripheral occlusive arterial disease；Or
It loses weight or prevents weight gain or promote weight loss；Or
Prevent, slow down, postpone or treat pancreatic beta cell degenerate and/or Pancreatic beta cells function reduce, and/or improve and/ Or restores the function of pancreatic beta cell and/or restore pancreatic insulin secreting function；Or
Prevent, slow down, postpone or treat disease or illness caused by liver fat extremely accumulation；Or
It keeps and/or improves insulin sensitivity and/or treat or prevent hyperinsulinemia and/or insulin resistance.
23. the purposes of the method or technique scheme 22 of any one of technical solution 17-21, the wherein patient are to suffer from after diagnosing There is the individual of one or more illnesss selected from overweight, obesity, visceral obesity and abdominal obesity.
24. the purposes of the method or technique scheme 22 of any one of technical solution 17-21, the wherein patient are display one The individual of kind, two or more following illnesss：
(a) fasting blood-glucose or serum glucose concentration are more than 100mg/dL, especially greater than 125mg/dL；
(b) Post-prandial plasma glucose is equal to or more than 140mg/dL；
(c) HbA1c values are equal to or more than 6.5%, are especially equal to or more than 7.0%.
25. the purposes of the method or technique scheme 22 of any one of technical solution 17-21, the wherein patient are to occur one Kind, two kinds, the individual of three kinds or a variety of following illnesss：
(a) obesity, visceral obesity and/or abdominal obesity,
(b) triglycerides blood content >=150mg/dL,
(c) female patient HDL- cholesterol blood levels<40mg/dL and male patient<50mg/dL,
(d) systolic pressure >=130mm Hg and diastolic pressure >=85mm Hg,
(e) fasting blood-glucose content >=100mg/dL.
26. the purposes of the method or technique scheme 22 of any one of technical solution 17-21, the wherein patient although into Row diet and exercise therapy although have carried out the monotherapy of antidiabetic but glycemic control is still insufficient.

Claims (6)

1. solid pharmaceutical dosage formulation, the BI 1356 for being 5mg it includes content as the first active pharmaceutical ingredients and content is 10mg Or the chloro- 4- of 1- (β-D- glucopyranose -1- bases) -2- [4- ((S)-tetrahydrofuran -3- bases oxygroup)-benzyl]-benzene of 25mg is made For the second active pharmaceutical ingredients,
The wherein described solid pharmaceutical dosage formulation includes
0.5-25% active pharmaceutical ingredients,
The one or more diluents of 40-88%,
The one or more adhesives of 0.5-20%, and
The one or more disintegrants of 0.5-20%,
Wherein percentage is the weight percent of total composition,
Wherein described one or more diluents are selected from mannitol and pregelatinized starch,
Wherein described one or more adhesives are selected from copolyvidone and/or pregelatinized starch,
Wherein described one or more disintegrants are selected from cornstarch, pregelatinized starch and Crospovidone,
The wherein described solid pharmaceutical dosage formulation is individual layer tablet, and two of which active pharmaceutical ingredients are present in the single layer,
Wherein the size distribution of second active ingredient is 1 μm<X90<200 μm, and
Wherein in dissolution is tested, after 45 mins, at least first active pharmaceutical ingredients of 75 weight % and at least 75 weights Second active pharmaceutical ingredients dissolving of % is measured,
Wherein described " BI 1356 " refers to BI 1356 and its pharmaceutically acceptable salt.
2. the solid pharmaceutical dosage formulation of claim 1, also includes
The one or more lubricants of 0.1-15%,
Wherein percentage is the weight percent of total composition.
3. the solid pharmaceutical dosage formulation of claim 2, wherein one or more lubricants are selected from：Talcum powder；Polyethylene glycol, especially It is polyethylene glycol of the molecular weight in about 4400 to about 9000 ranges；Rilanit special；Aliphatic acid and fatty acid salt, in particular Its calcium salt, magnesium salts, sodium salt or sylvite, such as behenic acid calcium, calcium stearate, sodium stearyl fumarate or magnesium stearate.
4. the solid pharmaceutical dosage formulation of claim 3, wherein one or more lubricants are selected from magnesium stearate and talcum powder.
5. the solid pharmaceutical dosage formulation of any one of the claims, in the shape of granule, capsule, tablet or thin membrane coated tablet Formula.
6. the solid pharmaceutical dosage formulation of any one of the claims, it is characterised in that in disintegration test, which exists It is disintegrated in 30 minutes.
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